Anemia
Conditions
Brief summary
This study will evaluate the efficacy and safety of different subcutaneous starting doses and dosing frequencies of Mircera in anemic patients with chronic kidney disease not yet on dialysis. The anticipated time on study treatment is 3-12 months and the target sample size is \<100 individuals.
Interventions
DRUGmethoxy polyethylene glycol-epoetin beta [Mircera]
Differing doses and frequencies of sc administration
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* adult patients \>=18 years of age; * chronic renal anemia; * not receiving renal replacement therapy.
Exclusion criteria
* women who are pregnant, breastfeeding or using unreliable birth control methods; * administration of any investigational drug within 30 days preceding the screening visit and during the run-in period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | From Baseline (Day -28 to Day 1) to EOIT (Week 19) | The primary efficacy variable was blood Hb level and its changes from Baseline (defined as the mean Hb of Screening assessment (SA) (Week -3), Weeks -2 and -1 of the Run-in period) over time during the core treatment period. For each participant, the primary efficacy parameter was the change in hemoglobin level over time based on regression slopes. All values until end-of-initial treatment (EOIT), defined as the last observed value before a dose change or blood transfusion, were included in the calculation of this endpoint. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | From Baseline (Day -28 to Day 1) to EOIT (Week 19) | Reticulocyte levels at EOIT under constant dosing regimen was analysed and reported. Baseline (Day -28 to Day 1) reticulocyte values were calculated as the mean of the SA (Week -3) and Run-in period (Weeks -2 and -1). For all participants, an EOIT value was calculated as the last observed reticulocyte count before a dose change or blood transfusion. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19. |
| Number of Participants With Any Serious Adverse Events and Any Adverse Events | Up to Week 125 | An Adverse Events (AEs) is defined as 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. Serious Adverse Events (SAEs) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event in the investigator's judgment or requires intervention to prevent one or other of these outcomes. The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time all results for the two long term safety periods were displayed by dose schedule group only. |
| Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | From Baseline (Day -28 to Day 1) to EOIT (Week 19) | Hematocrit (Hct) levels at end of initial treatment under constant dosing regimen were reported. Baseline (Day -28 to Day 1) Hct values was calculated as the mean of the SA (Week -3) and Run-in period (Weeks -2 and -1). For all participants, an EOIT value was calculated as the last observed Hct value before a dose change or blood transfusion. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19. |
| Heart Rate Over Time | Up to Week 125 | Heart rate was defined as the measure of heart beats per minute (bpm). The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time all results for the two long term safety periods were displayed by dose schedule group only. |
| Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | From Baseline (Day -28 to Day 1) to Week 125 | Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) is calculated as the end of treatment values minus the Baseline value. Baseline (Day -28 to Day 1) values were calculated as the mean of the SA (Week -3) and Run-in period (Week -2 and Week -1). |
| Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Up to Week 125 | Marked abnormality was defined as above and/or below a value (according to the Roche specified limits) which was considered to be potentially clinically relevant. The Roche reference range are: white blood cells (WBC) (3.0-18.0 10\^9 cells/L), platelets (100-550 10\^9 cells/L), alanine aminotransferase (ALT) \[0-110 units per litre (U/L)\], alkaline phosphatase (ALP) (0-220 U/L), aspartate aminotransferase (AST) (0-80 U/L), albumin \>= 30 g/L, phosphate \[0.75 - 1.60 millimoles per liter (mmol/L)\], potassium (2.9 - 5.8 mmol/L), total bilirubin (0-17 µmol/L), lymphocytes (1- 4.80 10\^9 cells/L), eosinophils (0 - 0.45 10\^9 cells/L), monocytes (0 - 0.8 10\^9 cells/L), and neutrophils (1.80 - 7.70 10\^9 cells/L). The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time, all results for the two long term safety periods were displayed by dose schedule group only. |
Countries
Canada, Mexico, Poland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted across 15 centers in 5 countries from 07 March 2002 until 23 November 2004 (last date of extension Year 2)
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) Eligible participants received RO0503821 at a dose of 0.15 mcg/kg SC once every week to complete the dosage of 0.9 mcg/kg up to 6 weeks (Week 1 to Week 6). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 6 |
| Cohort 2 (RO0503821,0.3 mcg/kg 1x/Week) Eligible participants received RO0503821 at a dose of 0.3 mcg/kg SC once every week to complete the dosage of 1.8 mcg/kg up to 6 weeks (Week 7 to Week 12). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 6 |
| Cohort 3 (RO0503821,0.6 mcg/kg 1x/Week) Eligible participants received RO0503821 at a dose of 0.6 mcg/kg SC once every week, to complete the dosage of 3.6 mcg/kg up to 6 weeks (Week 13 to Week 18). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 10 |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) Eligible participants received RO0503821 at a dose of 0.3 mcg/kg SC once every two week, to complete the dosage of 0.9 mcg/kg up to 6 weeks (Week 1 to Week 6). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period | 6 |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) Eligible participants received RO0503821 at a dose of 0.6 mcg/kg SC once every two week, to complete the dosage of 1.8 mcg/kg up to 6 weeks (Week 7 to Week 12). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 6 |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) Eligible participants received RO0503821 at a dose of 1.2 mcg/kg SC once every two week, to complete the dosage of 3.6 mcg/kg up to 6 weeks (Week 13 to Week 18). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 9 |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) Eligible participants received RO0503821 at a dose of 0.45 mcg/kg SC once every three week, to complete the dosage of 0.9 mcg/kg up to 6 weeks (Week 1 to Week 6). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 6 |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) Eligible participants received RO0503821 at a dose of 0.9 mcg/kg SC once every three week, to complete the dosage of 1.8 mcg/kg up to 6 weeks (Week 7 to Week 12). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 6 |
| Cohort 9 (RO0503821,1.8 mcg/kg 1x/3 Week) Eligible participants received RO0503821 at a dose of 1.8 mcg/kg SC once every three week, to complete the dosage of 3.6 mcg/kg up to 6 weeks (Week 13 to Week 18). Participants were followed-up for one week post the treatment period. During extension Years 1 and 2, the participants remained at the same frequency of administration as that of core treatment period. | 10 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Core Treatment | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Core Treatment | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Extension Year 1 | Early withdrawals | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 4 |
| Extension Year 2 | Early withdrawals | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Cohort 2 (RO0503821,0.3 mcg/kg 1x/Week) | Cohort 3 (RO0503821,0.6 mcg/kg 1x/Week) | Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | Cohort 9 (RO0503821,1.8 mcg/kg 1x/3 Week) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 58.2 Years STANDARD_DEVIATION 21.66 | 70.0 Years STANDARD_DEVIATION 13.75 | 58.0 Years STANDARD_DEVIATION 16.55 | 60.3 Years STANDARD_DEVIATION 16.8 | 62.7 Years STANDARD_DEVIATION 21.29 | 62.3 Years STANDARD_DEVIATION 12.63 | 66.5 Years STANDARD_DEVIATION 9.42 | 54.5 Years STANDARD_DEVIATION 16.85 | 58.3 Years STANDARD_DEVIATION 18.42 | 60.9 Years STANDARD_DEVIATION 16.2 |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 6 Participants | 4 Participants | 5 Participants | 6 Participants | 4 Participants | 5 Participants | 4 Participants | 42 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 6 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 22 | 18 / 21 | 22 / 22 |
| serious Total, serious adverse events | 11 / 22 | 9 / 21 | 12 / 22 |
Outcome results
Primary
The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes
The primary efficacy variable was blood Hb level and its changes from Baseline (defined as the mean Hb of Screening assessment (SA) (Week -3), Weeks -2 and -1 of the Run-in period) over time during the core treatment period. For each participant, the primary efficacy parameter was the change in hemoglobin level over time based on regression slopes. All values until end-of-initial treatment (EOIT), defined as the last observed value before a dose change or blood transfusion, were included in the calculation of this endpoint. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19.
Time frame: From Baseline (Day -28 to Day 1) to EOIT (Week 19)
Population: The Intent-to-Treat (ITT) population was defined as all randomized participants. Maximum number of participants with available data was reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 0.48 gram/deciliter (g/dL) |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 1.08 gram/deciliter (g/dL) |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 1.34 gram/deciliter (g/dL) |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 0.17 gram/deciliter (g/dL) |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 0.27 gram/deciliter (g/dL) |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 2.17 gram/deciliter (g/dL) |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 0.41 gram/deciliter (g/dL) |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 0.83 gram/deciliter (g/dL) |
| Cohort 9 (RO0503821, 1.8 mcg/kg 1x/3 Week) | The Change in Hemoglobin Over Time Between Baseline and End of Initial Treatment Based on Individual Regression Slopes | 1.28 gram/deciliter (g/dL) |
Comparison: All cohorts with dosing frequency 1X/ Week95% CI: [0.534, 1.425]
Comparison: All cohorts with dosing frequency 1X/ 2Week95% CI: [0.395, 1.307]
Comparison: All cohorts with dosing frequency 1X /3 Week95% CI: [0.488, 1.377]
Secondary
Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure
Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP) is calculated as the end of treatment values minus the Baseline value. Baseline (Day -28 to Day 1) values were calculated as the mean of the SA (Week -3) and Run-in period (Week -2 and Week -1).
Time frame: From Baseline (Day -28 to Day 1) to Week 125
Population: The safety population was considered for analysis which included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 2 mmHg | Standard Deviation 10.5 |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 12 mmHg | Standard Deviation 20.2 |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 2 mmHg | Standard Deviation 15.9 |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 5 mmHg | Standard Deviation 6.6 |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 5 mmHg | Standard Deviation 16.7 |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 6 mmHg | Standard Deviation 5.9 |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 6 mmHg | Standard Deviation 13.7 |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 2 mmHg | Standard Deviation 16.7 |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 8 mmHg | Standard Deviation 3.8 |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 2 mmHg | Standard Deviation 9.4 |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | -11 mmHg | Standard Deviation 16.3 |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | -3 mmHg | Standard Deviation 8.3 |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 6 mmHg | Standard Deviation 16.5 |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 6 mmHg | Standard Deviation 10.3 |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | 3 mmHg | Standard Deviation 10 |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | -2 mmHg | Standard Deviation 12.9 |
| Cohort 9 (RO0503821, 1.8 mcg/kg 1x/3 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | DBP | 4 mmHg | Standard Deviation 10.3 |
| Cohort 9 (RO0503821, 1.8 mcg/kg 1x/3 Week) | Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure | SBP | -3 mmHg | Standard Deviation 25.5 |
Secondary
Heart Rate Over Time
Heart rate was defined as the measure of heart beats per minute (bpm). The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time all results for the two long term safety periods were displayed by dose schedule group only.
Time frame: Up to Week 125
Population: The safety population was considered for analysis which included all participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Heart Rate Over Time | 65.6 bpm | Standard Deviation 4.3 |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Heart Rate Over Time | 68.4 bpm | Standard Deviation 9.8 |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Heart Rate Over Time | 75.4 bpm | Standard Deviation 10.4 |
Secondary
Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen
Hematocrit (Hct) levels at end of initial treatment under constant dosing regimen were reported. Baseline (Day -28 to Day 1) Hct values was calculated as the mean of the SA (Week -3) and Run-in period (Weeks -2 and -1). For all participants, an EOIT value was calculated as the last observed Hct value before a dose change or blood transfusion. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19.
Time frame: From Baseline (Day -28 to Day 1) to EOIT (Week 19)
Population: The ITT population was defined as all randomized participants. Maximum number of participants with available data was reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 31.10 g/dL |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 39.10 g/dL |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 36.95 g/dL |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 28.40 g/dL |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 34.70 g/dL |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 40.50 g/dL |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 32.70 g/dL |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 37.75 g/dL |
| Cohort 9 (RO0503821, 1.8 mcg/kg 1x/3 Week) | Hematocrit Levels at End of Initial Treatment Under Constant Dosing Regimen | 39 g/dL |
Secondary
Number of Participants With Any Serious Adverse Events and Any Adverse Events
An Adverse Events (AEs) is defined as 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. Serious Adverse Events (SAEs) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is a significant medical event in the investigator's judgment or requires intervention to prevent one or other of these outcomes. The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time all results for the two long term safety periods were displayed by dose schedule group only.
Time frame: Up to Week 125
Population: The safety population was considered for analysis which included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with SAEs | 11 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with AEs | 22 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with SAEs | 9 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with AEs | 21 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with SAEs | 12 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Any Serious Adverse Events and Any Adverse Events | Participants with AEs | 22 participants |
Secondary
Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time
Marked abnormality was defined as above and/or below a value (according to the Roche specified limits) which was considered to be potentially clinically relevant. The Roche reference range are: white blood cells (WBC) (3.0-18.0 10\^9 cells/L), platelets (100-550 10\^9 cells/L), alanine aminotransferase (ALT) \[0-110 units per litre (U/L)\], alkaline phosphatase (ALP) (0-220 U/L), aspartate aminotransferase (AST) (0-80 U/L), albumin \>= 30 g/L, phosphate \[0.75 - 1.60 millimoles per liter (mmol/L)\], potassium (2.9 - 5.8 mmol/L), total bilirubin (0-17 µmol/L), lymphocytes (1- 4.80 10\^9 cells/L), eosinophils (0 - 0.45 10\^9 cells/L), monocytes (0 - 0.8 10\^9 cells/L), and neutrophils (1.80 - 7.70 10\^9 cells/L). The study design tested 3 different starting dose conversion factors at 3 different dosing schedules during the core study period. As study drug doses can be modified continually over time, all results for the two long term safety periods were displayed by dose schedule group only.
Time frame: Up to Week 125
Population: The safety population was considered for analysis which included all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - Low, n = 12, 13, 14 | 2 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - High, n = 15, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Lymphocytes - Low, n = 15, 15, 19 | 2 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - Low, n = 16, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - Low, n = 15, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - High, n = 22, 21, 22 | 3 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | WBC - High, n = 16, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALT - High, n = 22, 21, 22 | 1 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - High , n = 12, 13, 14 | 7 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Monocytes - High, n = 15, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALP - High, n = 22, 21, 22 | 1 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - Low, n = 22, 21, 22 | 1 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Eosinophils - High, n = 15, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | AST - High, n = 22, 21, 22 | 2 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Albumin - Low, n = 22, 21, 22 | 2 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - High, n = 16, 15, 19 | 0 participants |
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Total bilirubin - High, n = 22, 21, 22 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - Low, n = 16, 15, 19 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Albumin - Low, n = 22, 21, 22 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - High , n = 12, 13, 14 | 6 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Lymphocytes - Low, n = 15, 15, 19 | 2 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - Low, n = 12, 13, 14 | 1 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - High, n = 22, 21, 22 | 2 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - Low, n = 22, 21, 22 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Monocytes - High, n = 15, 15, 19 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Total bilirubin - High, n = 22, 21, 22 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - High, n = 15, 15, 19 | 3 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - High, n = 16, 15, 19 | 1 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - Low, n = 15, 15, 19 | 2 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALT - High, n = 22, 21, 22 | 1 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | WBC - High, n = 16, 15, 19 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALP - High, n = 22, 21, 22 | 0 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | AST - High, n = 22, 21, 22 | 1 participants |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Eosinophils - High, n = 15, 15, 19 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - Low, n = 22, 21, 22 | 0 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - High, n = 16, 15, 19 | 0 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Platelets - Low, n = 16, 15, 19 | 3 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Eosinophils - High, n = 15, 15, 19 | 2 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Lymphocytes - Low, n = 15, 15, 19 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Monocytes - High, n = 15, 15, 19 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - High, n = 15, 15, 19 | 3 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Neutrophils - Low, n = 15, 15, 19 | 0 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALT - High, n = 22, 21, 22 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | ALP - High, n = 22, 21, 22 | 2 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | AST - High, n = 22, 21, 22 | 2 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Total bilirubin - High, n = 22, 21, 22 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Albumin - Low, n = 22, 21, 22 | 2 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - High , n = 12, 13, 14 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Phosphate - Low, n = 12, 13, 14 | 1 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | Potassium - High, n = 22, 21, 22 | 2 participants |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Number of Participants With Marked Laboratory Abnormalities for Blood Chemistry and Electrolytes Over Time | WBC - High, n = 16, 15, 19 | 1 participants |
Secondary
Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen
Reticulocyte levels at EOIT under constant dosing regimen was analysed and reported. Baseline (Day -28 to Day 1) reticulocyte values were calculated as the mean of the SA (Week -3) and Run-in period (Weeks -2 and -1). For all participants, an EOIT value was calculated as the last observed reticulocyte count before a dose change or blood transfusion. For participants without any dose adjustments, the EOIT value was identical to the value for Week 19.
Time frame: From Baseline (Day -28 to Day 1) to EOIT (Week 19)
Population: The ITT population was defined as all randomized participants. Maximum number of participants with available data was reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (RO0503821, 0.15 mcg/kg 1x/Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 71.80 Cells x10^3/UL |
| Cohort 2 (RO0503821, 0.3 mcg/kg 1x/Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 46.30 Cells x10^3/UL |
| Cohort 3 (RO0503821, 0.6 mcg/kg 1x/Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 44.70 Cells x10^3/UL |
| Cohort 4 (RO0503821, 0.3 mcg/kg 1x/2 Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 51.80 Cells x10^3/UL |
| Cohort 5 (RO0503821, 0.6 mcg/kg 1x/2Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 72.80 Cells x10^3/UL |
| Cohort 6 (RO0503821, 1.2 mcg/kg 1x/2 Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 59.20 Cells x10^3/UL |
| Cohort 7 (RO0503821, 0.45 mcg/kg 1x/3 Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 25.20 Cells x10^3/UL |
| Cohort 8 (RO0503821, 0.9 mcg/kg 1x/3Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 38.45 Cells x10^3/UL |
| Cohort 9 (RO0503821, 1.8 mcg/kg 1x/3 Week) | Reticulocyte Count at End of Initial Treatment Under Constant Dosing Regimen | 56.20 Cells x10^3/UL |