Anemia
Conditions
Brief summary
This study will determine the appropriate dose and frequency of administration of sc Mircera maintenance therapy in dialysis patients with chronic renal anemia who were previously receiving sc epoetin alfa or beta. The anticipated time on study treatment is 3-12 months and the target sample size is 100-500 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; * on dialysis (hemodialysis or peritoneal dialysis) therapy for at least 3 months; * receiving sc epoetin alfa or beta for at least 3 months prior to the run-in period.
Exclusion criteria
* women who are pregnant, breastfeeding or using unreliable birth control methods; * use of any investigational drug within 30 days preceding the run-in phase, or during the run-in or study treatment period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | From Baseline (Day -28 to Day 1) to EOIT (Week 19 or Week 21) | Median change from Baseline in hemoglobin (Hb) levels to end of initial treatment (EOIT) under constant dosing regimen was reported. For ease of interpretation, all individual slope values were multiplied by 42 to give an estimate of change in Hb values over six weeks. Baseline (Day -28 to Day 1) Hb values was calculated as the mean of the screening assessment (SA) and run-in period (Week -2 and -1). For all participants, an EOIT value was calculated as the last observed Hb value before a dose change or blood transfusion. For participants without any dose adjustments or blood transfusion, the EOIT value was identical to the Week 19 (or Week 21) value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | From Baseline (Day -28 to Day 1) to EOIT (Week 19 or Week 21) | Median change from Baseline in hematocrit (Hct) levels to end of initial treatment under constant dosing regimen was reported. Baseline (Day -28 to Day 1) Hct values was calculated as the mean of the SA 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 or blood transfusion, the EOIT value was identical to the Week 19 (or Week 21) value. |
| Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | From Baseline (Day -28 to Day 1) to Week 126 | Mean 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) value is the measurements taken at screening assessment and run-in period (Weeks -2 and -1). |
| Mean Change in Pulse Rate | Up to Week 126 | Mean change in pulse rate was reported. |
| Number of Participants With Marked Laboratory Abnormalities | Up to Week 126 | Participants with marked laboratory abnormalities were reported. Marked abnormality criteria: Serum glutamic oxaloacetic transaminase (SGOT); high \>25 units per litre (U/L), albumin (low \< 31 grams per litre \[g/L\]), total protein (\< 60 g/L), phosphate (high \>1.45 millimoles per litre \[mmol/L\]); Low \<0.84 mmol/L), potassium (high \>5 mmol/L; Low \<3.5 mmol/L), platelets (low:\<150×10\^9/L), White blood cells (\[WBCs\]); high: 10.8×10\^9/L and Low:4.3×10\^9/L), basophils (high:\>0.15×10\^9/L), eosinophils (high:\>0.70×10\^9/L), lymphocytes (low:\<1.50×10\^9/L), and neutrophils (low:\<1.83×10\^9/L). |
| Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Up to Week 126 | 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. |
Countries
Germany, Italy, Spain, United States
Participant flow
Recruitment details
A total of 137 participants were enrolled in this study conducted from 15 October 2001 to 7 July 2003 (core study period) and 19 September 2002 to 7 July 2005 (extension study period) at 22 centers (8 in Italy, 6 in the US, 4 in Germany, and 4 in Spain).
Participants by arm
| Arm | Count |
|---|---|
| Cohort A (0.4/150, 1x/ Week) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.4/150 mcg/kg of the previous weekly ESA dose, (equal to 50% assumed equi-effective dose) once weekly up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 16 |
| Cohort B (0.4/150, 1x/ 3 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.4/150 mcg/kg of the previous weekly ESA dose, (equal to 50% assumed equi-effective dose) once every three weeks up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 15 |
| Cohort C (0.4/150, 1x/ 4 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.4/150 mcg/kg of the previous weekly ESA dose, (equal to 50% assumed equi-effective dose) once every four weeks up to 21 weeks. After 21 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 15 |
| Cohort D (0.8/150, 1x/ Week) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.8/150 mcg/kg of the previous weekly ESA dose, (equal to 100% assumed equi-effective dose) once weekly up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 16 |
| Cohort E (0.8/150, 1x/ 3 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.8/150 mcg/kg of the previous weekly ESA dose, (equal to 100% assumed equi-effective dose) once every three weeks up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 16 |
| Cohort F (0.8/150, 1x/ 4 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 0.8/150 mcg/kg of the previous weekly ESA dose, (equal to 100% assumed equi-effective dose) once every four weeks up to 21 weeks. After 21 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 12 |
| Cohort G (1.2/150, 1x/ Week) Eligible participants were administered RO0503821 SC using a dose conversion factor of 1.2/150 mcg/kg of the previous weekly ESA dose, (equal to 150% assumed equi-effective dose) once weekly up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 16 |
| Cohort H (1.2/150, 1x/ 3 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 1.2/150 mcg/kg of the previous weekly ESA dose, (equal to 150% assumed equi-effective dose) once every three weeks up to 19 weeks. After 19 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 15 |
| Cohort I (1.2/150, 1x/ 4 Weeks) Eligible participants were administered RO0503821 SC using a dose conversion factor of 1.2/150 mcg/kg of the previous weekly ESA dose, (equal to 150% assumed equi-effective dose) once every four weeks up to 21 weeks. After 21 weeks of core treatment period, participants were followed-up for two optional treatment extension periods (54 weeks each). | 16 |
| Total | 137 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Core Period | Early Withdrawals | 2 | 2 | 1 | 1 | 0 | 0 | 4 | 1 | 0 | 0 | 0 | 0 |
| Extension Year 1 | Early Withdrawals | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 2 | 10 |
| Extension Year 2 | Early Withdrawals | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 5 | 3 |
Baseline characteristics
| Characteristic | Cohort A (0.4/150, 1x/ Week) | Cohort B (0.4/150, 1x/ 3 Weeks) | Cohort C (0.4/150, 1x/ 4 Weeks) | Cohort D (0.8/150, 1x/ Week) | Cohort E (0.8/150, 1x/ 3 Weeks) | Cohort F (0.8/150, 1x/ 4 Weeks) | Cohort G (1.2/150, 1x/ Week) | Cohort H (1.2/150, 1x/ 3 Weeks) | Cohort I (1.2/150, 1x/ 4 Weeks) | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 13.03 | 65.6 years STANDARD_DEVIATION 11.29 | 64.8 years STANDARD_DEVIATION 10.28 | 61.8 years STANDARD_DEVIATION 13.51 | 64.1 years STANDARD_DEVIATION 12.83 | 67.3 years STANDARD_DEVIATION 13.3 | 62.7 years STANDARD_DEVIATION 13.74 | 58.9 years STANDARD_DEVIATION 13.12 | 64.1 years STANDARD_DEVIATION 13.34 | 63.9 years STANDARD_DEVIATION 12.63 |
| Gender Female | 5 Participants | 8 Participants | 5 Participants | 6 Participants | 5 Participants | 7 Participants | 4 Participants | 5 Participants | 7 Participants | 52 Participants |
| Gender Male | 11 Participants | 7 Participants | 10 Participants | 10 Participants | 11 Participants | 5 Participants | 12 Participants | 10 Participants | 9 Participants | 85 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 | 36 / 48 | 30 / 46 | 39 / 43 |
| serious Total, serious adverse events | 15 / 48 | 13 / 46 | 20 / 43 |
Outcome results
Primary
Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen
Median change from Baseline in hemoglobin (Hb) levels to end of initial treatment (EOIT) under constant dosing regimen was reported. For ease of interpretation, all individual slope values were multiplied by 42 to give an estimate of change in Hb values over six weeks. Baseline (Day -28 to Day 1) Hb values was calculated as the mean of the screening assessment (SA) and run-in period (Week -2 and -1). For all participants, an EOIT value was calculated as the last observed Hb value before a dose change or blood transfusion. For participants without any dose adjustments or blood transfusion, the EOIT value was identical to the Week 19 (or Week 21) value.
Time frame: From Baseline (Day -28 to Day 1) to EOIT (Week 19 or Week 21)
Population: The ITT population was considered for analysis which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (0.4/150, 1x/ Week) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.80 gram per deciliter |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.60 gram per deciliter |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.29 gram per deciliter |
| Cohort D (0.8/150, 1x/ Week) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.02 gram per deciliter |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.14 gram per deciliter |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.28 gram per deciliter |
| Cohort G (1.2/150, 1x/ Week) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.65 gram per deciliter |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.33 gram per deciliter |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Median Change From Baseline in Hemoglobin Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.22 gram per deciliter |
Comparison: All cohorts with dosing frequency 1x/ week (0.4, 0.8 and 1.2 dose group)90% CI: [0.73, 0.9]
Comparison: All cohorts with dosing frequency 1x/ 3 weeks (0.4, 0.8 and 1.2 dose group)90% CI: [0.55, 0.86]
Comparison: All cohorts with dosing frequency 1x/ 4 weeks (0.4, 0.8 and 1.2 dose group)90% CI: [0.81, 1.09]
Secondary
Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis
Mean 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) value is the measurements taken at screening assessment and run-in period (Weeks -2 and -1).
Time frame: From Baseline (Day -28 to Day 1) to Week 126
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 A (0.4/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -1 Millimeters of Mercury | Standard Deviation 25.5 |
| Cohort A (0.4/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | -3 Millimeters of Mercury | Standard Deviation 14.6 |
| Cohort A (0.4/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | -1 Millimeters of Mercury | Standard Deviation 14.2 |
| Cohort A (0.4/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | 0 Millimeters of Mercury | Standard Deviation 24.4 |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | 4 Millimeters of Mercury | Standard Deviation 10.4 |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | 7 Millimeters of Mercury | Standard Deviation 15.5 |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | 10 Millimeters of Mercury | Standard Deviation 34.3 |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | 1 Millimeters of Mercury | Standard Deviation 9 |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | 3 Millimeters of Mercury | Standard Deviation 12.5 |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | -1 Millimeters of Mercury | Standard Deviation 12.9 |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | 1 Millimeters of Mercury | Standard Deviation 26.9 |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | 2 Millimeters of Mercury | Standard Deviation 30.4 |
| Cohort D (0.8/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -8 Millimeters of Mercury | Standard Deviation 18.1 |
| Cohort D (0.8/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | -4 Millimeters of Mercury | Standard Deviation 25.2 |
| Cohort D (0.8/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | -3 Millimeters of Mercury | Standard Deviation 15.8 |
| Cohort D (0.8/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | -3 Millimeters of Mercury | Standard Deviation 11.4 |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -4 Millimeters of Mercury | Standard Deviation 10.8 |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | 0 Millimeters of Mercury | Standard Deviation 11.1 |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | 7 Millimeters of Mercury | Standard Deviation 17.1 |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | -2 Millimeters of Mercury | Standard Deviation 9.4 |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | 2 Millimeters of Mercury | Standard Deviation 13.4 |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | -5 Millimeters of Mercury | Standard Deviation 27.6 |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -6 Millimeters of Mercury | Standard Deviation 20.3 |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | 2 Millimeters of Mercury | Standard Deviation 12.9 |
| Cohort G (1.2/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | -3 Millimeters of Mercury | Standard Deviation 12.2 |
| Cohort G (1.2/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | 0 Millimeters of Mercury | Standard Deviation 25 |
| Cohort G (1.2/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -2 Millimeters of Mercury | Standard Deviation 21.4 |
| Cohort G (1.2/150, 1x/ Week) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | -3 Millimeters of Mercury | Standard Deviation 11.9 |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | -1 Millimeters of Mercury | Standard Deviation 27.1 |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | 1 Millimeters of Mercury | Standard Deviation 18.6 |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | -0 Millimeters of Mercury | Standard Deviation 11.4 |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | 5 Millimeters of Mercury | Standard Deviation 10.2 |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP after dialysis | -7 Millimeters of Mercury | Standard Deviation 18.2 |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | SBP before dialysis | -7 Millimeters of Mercury | Standard Deviation 20 |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP after dialysis | -5 Millimeters of Mercury | Standard Deviation 10.3 |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Before and After Dialysis | DBP before dialysis | 1 Millimeters of Mercury | Standard Deviation 8.6 |
Secondary
Mean Change in Pulse Rate
Mean change in pulse rate was reported.
Time frame: Up to Week 126
Population: The safety population was considered for analysis which included all participants who received at least one dose of study drug. Participants with available data at the time of evaluation were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A (0.4/150, 1x/ Week) | Mean Change in Pulse Rate | -6 Beats per minute | Standard Deviation 8.8 |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Mean Change in Pulse Rate | -2 Beats per minute | Standard Deviation 9.1 |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Mean Change in Pulse Rate | 7 Beats per minute | Standard Deviation 9.1 |
| Cohort D (0.8/150, 1x/ Week) | Mean Change in Pulse Rate | -1 Beats per minute | Standard Deviation 13.7 |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Mean Change in Pulse Rate | -1 Beats per minute | Standard Deviation 7.7 |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Mean Change in Pulse Rate | 2 Beats per minute | Standard Deviation 8.1 |
| Cohort G (1.2/150, 1x/ Week) | Mean Change in Pulse Rate | 2 Beats per minute | Standard Deviation 9.9 |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Mean Change in Pulse Rate | 0 Beats per minute | Standard Deviation 6.3 |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Mean Change in Pulse Rate | 1 Beats per minute | Standard Deviation 9.1 |
Secondary
Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen
Median change from Baseline in hematocrit (Hct) levels to end of initial treatment under constant dosing regimen was reported. Baseline (Day -28 to Day 1) Hct values was calculated as the mean of the SA 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 or blood transfusion, the EOIT value was identical to the Week 19 (or Week 21) value.
Time frame: From Baseline (Day -28 to Day 1) to EOIT (Week 19 or Week 21)
Population: The ITT population was considered for analysis which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort A (0.4/150, 1x/ Week) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | -2.45 Percentage of Hct |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | -1.95 Percentage of Hct |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.93 Percentage of Hct |
| Cohort D (0.8/150, 1x/ Week) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.25 Percentage of Hct |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.37 Percentage of Hct |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | -0.75 Percentage of Hct |
| Cohort G (1.2/150, 1x/ Week) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | 2.25 Percentage of Hct |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | 1.22 Percentage of Hct |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Median Change From Baseline in Hematocrit Levels to End of Initial Treatment Under Constant Dosing Regimen | 0.73 Percentage of Hct |
Secondary
Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths
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 126
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 A (0.4/150, 1x/ Week) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any SAEs | 15 Participants |
| Cohort A (0.4/150, 1x/ Week) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any AEs | 44 Participants |
| Cohort A (0.4/150, 1x/ Week) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Deaths | 7 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any SAEs | 13 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any AEs | 33 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Deaths | 4 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any AEs | 40 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Deaths | 10 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Any Adverse Events, Any Serious Adverse Events, And Deaths | Any SAEs | 20 Participants |
Secondary
Number of Participants With Marked Laboratory Abnormalities
Participants with marked laboratory abnormalities were reported. Marked abnormality criteria: Serum glutamic oxaloacetic transaminase (SGOT); high \>25 units per litre (U/L), albumin (low \< 31 grams per litre \[g/L\]), total protein (\< 60 g/L), phosphate (high \>1.45 millimoles per litre \[mmol/L\]); Low \<0.84 mmol/L), potassium (high \>5 mmol/L; Low \<3.5 mmol/L), platelets (low:\<150×10\^9/L), White blood cells (\[WBCs\]); high: 10.8×10\^9/L and Low:4.3×10\^9/L), basophils (high:\>0.15×10\^9/L), eosinophils (high:\>0.70×10\^9/L), lymphocytes (low:\<1.50×10\^9/L), and neutrophils (low:\<1.83×10\^9/L).
Time frame: Up to Week 126
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 A (0.4/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort A (0.4/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort A (0.4/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 1 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort B (0.4/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 1 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort C (0.4/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort D (0.8/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort D (0.8/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort D (0.8/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort E (0.8/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort F (0.8/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort G (1.2/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 1 Participants |
| Cohort G (1.2/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort G (1.2/150, 1x/ Week) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 0 Participants |
| Cohort H (1.2/150, 1x/ 3 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | SGOT, High | 0 Participants |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Total protein, Low | 0 Participants |
| Cohort I (1.2/150, 1x/ 4 Weeks) | Number of Participants With Marked Laboratory Abnormalities | Albumin, Low | 1 Participants |