Renal Anemia
Conditions
Brief summary
This sequential study will assess the efficacy and safety of multiple doses of intravenous (IV) methoxy polyethylene glycol-epoetin beta (MIRCERA), and will determine the optimum starting dose for maintenance treatment of anemia in children with chronic kidney disease on hemodialysis. Pediatric participants will remain on epoetin alfa, epoetin beta or darbepoetin alfa during the screening period, after which they will receive IV MIRCERA monthly, at a starting dose related to the previous weekly epoetin or darbepoetin alfa dose. Depending on the response achieved, another group may be selected to receive a higher or a lower dose.
Interventions
DRUGMethoxy Polyethylene Glycol-Epoetin Beta
Will be administered IV, every 4 weeks.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children aged 5-17 years (in Russia only: 12-17 years) with clinically stable chronic renal anemia * Hemodialysis for greater than or equal to (\>=) 8 weeks * Intravenous stable maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa for \>= 8 weeks before screening and with no weekly dose change \>= 25 percent (%) (increase or decrease) during the 2 weeks of screening
Exclusion criteria
* Overt gastrointestinal bleeding within 8 weeks before screening or during the screening period * Red blood cell (RBC) transfusions within 8 weeks before screening or during the screening period * Active malignant disease * Pure red cell aplasia (PRCA) or history of PRCA * Pregnant or lactating females * Sexually active participants: not willing to use reliable contraception during treatment and for 90 days following the end of treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average Hb Concentration Between Baseline and Evaluation Period | Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21) | A time adjusted average baseline Hb concentration for each individual was calculated using an area under the curve (AUC) approach from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The average evaluation period Hb concentration for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Week 17 to Week 21). The change in Hb concentration between the baseline and evaluation periods was calculated by subtracting the baseline Hb concentration from the evaluation period Hb concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Evaluation Period (Week 17 to Week 21) | The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21). |
| Number of Participants With Blood Transfusions | Baseline to Week 20 | — |
| Change in Average Reticulocyte Count Between the Baseline and Evaluation Period | Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21) | A time adjusted average baseline reticulocyte count for each individual was calculated using an AUC approach from all available reticulocyte counts taken during the baseline period (Day -20 to Day 1). The average evaluation period reticulocyte count for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Weeks 17 to 21). The change in reticulocyte count between the baseline and evaluation periods was calculated by subtracting the baseline reticulocyte count from the evaluation period reticulocyte count. Relative reticulocytes were recorded conversion to absolute values was performed. |
| Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb | Evaluation Period (Week 17 to Week 21) | Baseline Hb value was defined as the average Hb concentration from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21). |
| Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA | Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13 | Area under the serum concentration versus time curve over 672 hours. AUC0-672h represents area under the serum concentration versus time curve from time zero to end of dosing interval (AUC0-tau). |
| Time to Reach Cmax (Tmax) of MIRCERA | Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13 | Tmax was defined as the time (in hours) to achieve Cmax (Cmax was defined as the highest serum concentration observed over all sample collection timepoints \[as provided in timeframe\]). The median time, among all participants, was reported. |
| Apparent Terminal Phase Half-Life (t1/2) of MIRCERA | Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13 | t1/2 was defined as the time (in hours) measured (from all sample collection timepoints \[as provided in timeframe\]) for the serum concentration to decrease by one half. The t1/2 was calculated as natural logarithm of 2 divided by λz; where λz = terminal elimination rate constant. |
| Maximum Observed Serum Concentration (Cmax) of MIRCERA | Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13 | Cmax was defined as the highest serum concentration observed from all sample collection timepoints (as provided in timeframe) and was averaged out among participants and reported. |
Countries
Australia, Belgium, France, Germany, Hungary, Italy, Poland, Romania, Russia, Spain, Thailand, Ukraine
Participant flow
Pre-assignment details
A total of 112 participants were screened at 28 sites in 10 countries, of which 64 participants were enrolled (16 initially in MIRCERA Group 1 and then 48 in MIRCERA Group 2, following a preliminary analysis of MIRCERA Group 1).
Participants by arm
| Arm | Count |
|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group Participants received MIRCERA IV injection at a starting dose based on an intermediate conversion factor from their previous ESA dose (4 \* previous weekly epoetin dose \[IU\]/250 or 4 \* previous weekly darbepoetin alfa dose \[mcg\]/1.1) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks. | 16 |
| MIRCERA Group 2: High-Conversion-Factor Group Participants received MIRCERA IV injection based on a high conversion factor from their previous ESA dose (4 \* previous weekly epoetin dose \[IU\]/125 or 4 \* previous weekly darbepoetin alfa dose \[mcg\]/0.55) once every 4 weeks for 20 weeks. Participants who completed the 20 weeks of treatment and had Hb level within ± 1 g/dL of their baseline Hb level and within the target range of 10-12 g/dL, entered an optional 52-weeks safety extension period. During this period, the participants continued to receive MIRCERA IV injection once every 4 weeks. | 48 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Study Period (20 Weeks) | Admin/Other than specified | 0 | 2 |
| Core Study Period (20 Weeks) | Death | 0 | 1 |
| Core Study Period (20 Weeks) | Refused treatment/Did not cooperate | 0 | 1 |
| Core Study Period (20 Weeks) | Renal transplant | 4 | 9 |
| Extension Period (52 Weeks) | Admin/Other than specified | 0 | 2 |
| Extension Period (52 Weeks) | Renal transplant | 3 | 13 |
| Extension Period (52 Weeks) | Withdrew consent | 1 | 1 |
Baseline characteristics
| Characteristic | MIRCERA Group 1: Intermediate-Conversion-Factor Group | MIRCERA Group 2: High-Conversion-Factor Group | Total |
|---|---|---|---|
| Age, Continuous | 11.3 years STANDARD_DEVIATION 3.24 | 13.0 years STANDARD_DEVIATION 3.06 | 12.6 years STANDARD_DEVIATION 3.17 |
| Sex: Female, Male Female | 5 Participants | 25 Participants | 30 Participants |
| Sex: Female, Male Male | 11 Participants | 23 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 16 | 28 / 48 |
| serious Total, serious adverse events | 4 / 16 | 17 / 48 |
Outcome results
Primary
Change in Average Hb Concentration Between Baseline and Evaluation Period
A time adjusted average baseline Hb concentration for each individual was calculated using an area under the curve (AUC) approach from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The average evaluation period Hb concentration for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Week 17 to Week 21). The change in Hb concentration between the baseline and evaluation periods was calculated by subtracting the baseline Hb concentration from the evaluation period Hb concentration.
Time frame: Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21)
Population: ITT population. Hb values within 21 days after blood transfusion(s) were excluded from analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Change in Average Hb Concentration Between Baseline and Evaluation Period | Baseline (n=16,48) | 11.26 g/dL | Standard Deviation 0.496 |
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Change in Average Hb Concentration Between Baseline and Evaluation Period | Change at Evaluation Period (n=12,36) | -0.78 g/dL | Standard Deviation 1.237 |
| MIRCERA Group 2: High-Conversion-Factor Group | Change in Average Hb Concentration Between Baseline and Evaluation Period | Change at Evaluation Period (n=12,36) | -0.15 g/dL | Standard Deviation 1.014 |
| MIRCERA Group 2: High-Conversion-Factor Group | Change in Average Hb Concentration Between Baseline and Evaluation Period | Baseline (n=16,48) | 11.08 g/dL | Standard Deviation 0.493 |
Secondary
Apparent Terminal Phase Half-Life (t1/2) of MIRCERA
t1/2 was defined as the time (in hours) measured (from all sample collection timepoints \[as provided in timeframe\]) for the serum concentration to decrease by one half. The t1/2 was calculated as natural logarithm of 2 divided by λz; where λz = terminal elimination rate constant.
Time frame: Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
Population: PK evaluable population. Number of participants analyzed = participants evaluable for t1/2 assessments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Apparent Terminal Phase Half-Life (t1/2) of MIRCERA | 147 hours | Geometric Coefficient of Variation 30.1 |
| MIRCERA Group 2: High-Conversion-Factor Group | Apparent Terminal Phase Half-Life (t1/2) of MIRCERA | 121 hours | Geometric Coefficient of Variation 43.5 |
Secondary
Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA
Area under the serum concentration versus time curve over 672 hours. AUC0-672h represents area under the serum concentration versus time curve from time zero to end of dosing interval (AUC0-tau).
Time frame: Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
Population: PK evaluable population. Number of participants analyzed = participants with AUC0-672h assessment at specified time-points.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA | 3630000 picograms*hour/milliliter (pg*h/mL) | Geometric Coefficient of Variation 91.8 |
| MIRCERA Group 2: High-Conversion-Factor Group | Area Under the Serum Concentration-Time Curve From 0 to 672 Hours (AUC0-672h) of MIRCERA | 7170000 picograms*hour/milliliter (pg*h/mL) | Geometric Coefficient of Variation 140 |
Secondary
Change in Average Reticulocyte Count Between the Baseline and Evaluation Period
A time adjusted average baseline reticulocyte count for each individual was calculated using an AUC approach from all available reticulocyte counts taken during the baseline period (Day -20 to Day 1). The average evaluation period reticulocyte count for each individual was calculated using the same method, from all their available measurements taken during the evaluation period (Weeks 17 to 21). The change in reticulocyte count between the baseline and evaluation periods was calculated by subtracting the baseline reticulocyte count from the evaluation period reticulocyte count. Relative reticulocytes were recorded conversion to absolute values was performed.
Time frame: Baseline (Day -20 to Day 1), Evaluation Period (Week 17 to Week 21)
Population: ITT population. Reticulocyte values within 21 days after blood transfusion(s) were excluded from analysis. Here, number of participants analyzed = participants evaluable for this outcome measure and 'n' signifies number of participants evaluable at specified time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Change in Average Reticulocyte Count Between the Baseline and Evaluation Period | Baseline (n=15,48) | 46.08 10^3 cells/microliter | Standard Deviation 26.472 |
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Change in Average Reticulocyte Count Between the Baseline and Evaluation Period | Change at Evaluation Period (n=11,36) | 23.38 10^3 cells/microliter | Standard Deviation 29.279 |
| MIRCERA Group 2: High-Conversion-Factor Group | Change in Average Reticulocyte Count Between the Baseline and Evaluation Period | Baseline (n=15,48) | 43.70 10^3 cells/microliter | Standard Deviation 25.984 |
| MIRCERA Group 2: High-Conversion-Factor Group | Change in Average Reticulocyte Count Between the Baseline and Evaluation Period | Change at Evaluation Period (n=11,36) | 24.80 10^3 cells/microliter | Standard Deviation 32.428 |
Secondary
Maximum Observed Serum Concentration (Cmax) of MIRCERA
Cmax was defined as the highest serum concentration observed from all sample collection timepoints (as provided in timeframe) and was averaged out among participants and reported.
Time frame: Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
Population: Pharmacokinetic (PK) evaluable population included all enrolled participants who received at least one dose of study drug and had evaluable PK assessment. Here 'n' signifies number of participants evaluable at specified time-points.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Maximum Observed Serum Concentration (Cmax) of MIRCERA | 37700 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 74.5 |
| MIRCERA Group 2: High-Conversion-Factor Group | Maximum Observed Serum Concentration (Cmax) of MIRCERA | 66100 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 149.5 |
Secondary
Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL
The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21).
Time frame: Evaluation Period (Week 17 to Week 21)
Population: ITT population. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number of participants analyzed = participants with Hb concentration assessment at specified time-points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Above 12 g/dL | 0 participants |
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Within 10-12 g/dL | 9 participants |
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Below 10 g/dL | 3 participants |
| MIRCERA Group 2: High-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Above 12 g/dL | 3 participants |
| MIRCERA Group 2: High-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Within 10-12 g/dL | 29 participants |
| MIRCERA Group 2: High-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Above, Within or Below the Range of 10-12 g/dL | Below 10 g/dL | 4 participants |
Secondary
Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb
Baseline Hb value was defined as the average Hb concentration from all available Hb measurements taken during the baseline period (Day -20 to Day 1). The evaluation period Hb concentration was defined as the average Hb concentration from all available Hb measurements taken during the evaluation period (Week 17 to Week 21).
Time frame: Evaluation Period (Week 17 to Week 21)
Population: ITT population. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number of participants analyzed = participants with Hb concentration assessment at specified time-points.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb | 7 participants |
| MIRCERA Group 2: High-Conversion-Factor Group | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ±1 g/dL of Their Baseline Hb | 27 participants |
Secondary
Number of Participants With Blood Transfusions
Time frame: Baseline to Week 20
Population: ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Number of Participants With Blood Transfusions | 1 participants |
| MIRCERA Group 2: High-Conversion-Factor Group | Number of Participants With Blood Transfusions | 2 participants |
Secondary
Time to Reach Cmax (Tmax) of MIRCERA
Tmax was defined as the time (in hours) to achieve Cmax (Cmax was defined as the highest serum concentration observed over all sample collection timepoints \[as provided in timeframe\]). The median time, among all participants, was reported.
Time frame: Pre-dose (with 1 hour before drug administration) and 2, 48 hours post dose on Week 9, at Weeks 10, 11, and 12, pre-dose (with 1 hour before drug administration) on Week 13
Population: PK evaluable population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MIRCERA Group 1: Intermediate-Conversion-Factor Group | Time to Reach Cmax (Tmax) of MIRCERA | 2.00 hours |
| MIRCERA Group 2: High-Conversion-Factor Group | Time to Reach Cmax (Tmax) of MIRCERA | 2.00 hours |