Anemia
Conditions
Brief summary
BCD-131 is pegylated darbepoetin beta. BCD-131-2 is International Multicenter Randomized Open-Label Comparative Study (Phase II) of the Efficacy and Safety of BCD-131 and Mircera in Treatment of Anemia in Chronic Kidney Disease Patients on Dialysis.
Detailed description
The hypothesis of the study is that the efficacy of BCD-131 is equivalent to that of Mircera® based on the analysis of the primary endpoint (changes in the Hb level over the period of evaluation as compared to the baseline Hb level ) during the 21-week period of treatment. This study is a study of the maintenance treatment of anemia. The study will include up to 100 dialysis patients with stage 5D chronic kidney disease, established efficacy of dialysis and renal anemia without other causes of anemia, receiving erythropoiesis-stimulating agents (ESA) and reaching target hemoglobin levels.
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed written informed consent. * Men and women aged from 18 to 75 years (inclusive) on the day of signing informed consent; * End-stage kidney disease. * Need for dialysis for at least 3 months before signing informed consent. * Need for at least 12 hours on standard dialysis procedure weekly. * rHuEpo (epoetin alpha, epoetin beta, darbepoetin alpha) administration for at least 3 months before signing informed consent. * Regular rHuEpo (epoetin alfa, epoetin beta, darbepoetin alfa) administration 1, 2 or 3 times a week (stable dose, stable frequency) before signing informed consent. * Target hemoglobin level (100-120 g/l) for at least 3 months before signing informed consent. * Effective dialysis dose index (Kt/v) ≥1.2 for patients receiving hemodialysis and (Kt/v) ≥1.7 for patients receiving peritoneal dialysis. * TSAT ≥20%, Serum ferritin \>200 ng/ml. * Patients and their sexual partners with childbearing potential must implement reliable contraceptive measures during all the study treatment, starting 4 weeks prior to the administration of the first dose of investigational product until 4 weeks after the last dose of investigational product. This requirement does not apply to participants who have undergone surgical sterilization. Reliable contraceptive measures include two methods of contraception, including one barrier method/ * Patients should be able to follow the Protocol procedures
Exclusion criteria
* Any other causes of anemia except for renal anemia, including folate and B12 deficiency, chronic blood loss, aluminium intoxication, sickle-cell anemia, chronic disease anemia (CRP above 20 mg/l), refractory anemia with blast cells in peripheral blood. * Lupus nephritis of kidney disease due to systemic vasculitis. * Platelet count below 100х10\^9 cells/l. * Scheduled kidney transplant during study participation period. * Hypersensitivity to darbepoetin alfa or of any components of study drugs, or to Fe (III)-hydroxide-sucrose complex. * Vaccination less than 8 weeks before signing informed consent. * Liver cirrhosis with portal hypertension and/or splenomegaly and/or ascitis. * HIV infection, active HBV, HCV. * ALT, AST level above 3x ULN. * Congestive heart failure (Grade IV NYHA) * Resistant arterial hypertension. * Unstable angina. * Hemoglobinopathy, MDS, hematologic malignancy, PRCA. * Severe secondary hyperparathyroidism. * Gastrointestinal bleeding history. * Thrombotic events history (myocardial infarction, stroke, TIA, DVT, PATE) less than 6 months before signing informed consent. * Seizures, including epilepsy. * Major surgery in less than 1 month before signing informed consent * Blood transfusions in less than 3 months before signing informed consent. * Acute inflammatory diseases or exacerbations of chronic inflammation. * Severe psychiatric disorders and suicidal ideation and suicidal behavior. * History of malignancy, excluding appropriately treated basal cell carcinoma or cervical carcinoma in situ. * Alcohol or drug abuse. * Simultaneous participation in other trials or in less than 3 months before signing informed consent * Pregnancy of breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | Baseline - measurements on Screening (weeks -4 - 0) and on day 1; Evaluation period - weekly measures on weeks 21 to 23 | The baseline hemoglobin will be calculated as the arithmetic mean of hemoglobin values obtained at screening and at Visit 1. The final hemoglobin value during the evaluation period will be calculated as the arithmetic mean of hemoglobin values obtained at Week 21 and Week 23. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of BAb- and NAb-positive Patients | Week 9, 23 | Blood sampling for immunogenicity assessment (BAbs and NAbs) will be performed in all the patients included in the study before the first injection and then at Week 9 and Week 23. The immunogenicity endpoints will be analyzed after the completion of all periods of the study. |
| AUC(0-672 Hour) | 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1 | Area under the concentration curve from the moment of injection to 672 h \[28 days\]) |
| AUC(0-∞) | 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1, weeks 5, 9, 13, 17, 21 | Area under the concentration curve from the moment of injection to infinity |
| The Proportion of Patients Who Developed AEs/SAEs That, in the Investigator's Opinion, Are Related to BCD-131 | Week 23 | The proportion of patients, in each group, who developed СТСАЕ v. 4.03 Grade 3-4 AEs that, in the Investigator's opinion, are related to BCD-131 \- the proportion of patients, in each group, who discontinued the study due to AEs/SAEs |
| AUEC(0-672 Hour) | 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1 | Area under the effect curve from the drug injection to 672 h \[28 days\]) based on the change in the absolute reticulocyte count after the first injection of the test/reference drug |
| AC-Emax | day 28 | Maximum absolute reticulocyte count after the first injection of BCD-131/Mircera® |
| Cmax | 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1, weeks 5, 9, 13, 17, 21 | Maximum serum concentration of the drug product) after the first injection of the test/reference drug |
Countries
Belarus, Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio subcutaneously monthly
BCD-131: subcutaneously monthly | 25 |
| BCD-131 1,7 mcg/kg * Conversion Ratio subcutaneously monthly
BCD-131: subcutaneously monthly | 25 |
| Mircera subcutaneously monthly
Mircera: subcutaneously monthly | 25 |
| Total | 75 |
Baseline characteristics
| Characteristic | BCD-131 1,05 mcg/kg * Conversion Ratio | BCD-131 1,7 mcg/kg * Conversion Ratio | Mircera | Total |
|---|---|---|---|---|
| Age, Continuous | 60 years | 54 years | 47 years | 55 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 24 Participants | 25 Participants | 24 Participants | 73 Participants |
| Region of Enrollment Belarus | 5 participants | 1 participants | 2 participants | 8 participants |
| Region of Enrollment Russia | 20 participants | 24 participants | 23 participants | 67 participants |
| Sex: Female, Male Female | 14 Participants | 12 Participants | 11 Participants | 37 Participants |
| Sex: Female, Male Male | 11 Participants | 13 Participants | 14 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 2 / 25 | 0 / 25 |
| other Total, other adverse events | 13 / 25 | 16 / 25 | 15 / 25 |
| serious Total, serious adverse events | 6 / 25 | 4 / 25 | 3 / 25 |
Outcome results
Primary
Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period
The baseline hemoglobin will be calculated as the arithmetic mean of hemoglobin values obtained at screening and at Visit 1. The final hemoglobin value during the evaluation period will be calculated as the arithmetic mean of hemoglobin values obtained at Week 21 and Week 23.
Time frame: Baseline - measurements on Screening (weeks -4 - 0) and on day 1; Evaluation period - weekly measures on weeks 21 to 23
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | -3.25 g/L |
| BCD-131 1,7 mcg/kg * Conversion Ratio | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | 3.5 g/L |
| Mircera | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | -2.75 g/L |
Secondary
AC-Emax
Maximum absolute reticulocyte count after the first injection of BCD-131/Mircera®
Time frame: day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | AC-Emax | 96.650 (cells*10^9)/L | Standard Deviation 29.185 |
| BCD-131 1,7 mcg/kg * Conversion Ratio | AC-Emax | 107.047 (cells*10^9)/L | Standard Deviation 38.615 |
| Mircera | AC-Emax | 154.753 (cells*10^9)/L | Standard Deviation 58.729 |
Secondary
AUC(0-∞)
Area under the concentration curve from the moment of injection to infinity
Time frame: 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1, weeks 5, 9, 13, 17, 21
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | AUC(0-∞) | 65150.045 (mmol/L)*h |
| BCD-131 1,7 mcg/kg * Conversion Ratio | AUC(0-∞) | 81698.001 (mmol/L)*h |
| Mircera | AUC(0-∞) | 96259.513 (mmol/L)*h |
Secondary
AUC(0-672 Hour)
Area under the concentration curve from the moment of injection to 672 h \[28 days\])
Time frame: 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | AUC(0-672 Hour) | 51744.45 (mmol/L)*h |
| BCD-131 1,7 mcg/kg * Conversion Ratio | AUC(0-672 Hour) | 73948.8 (mmol/L)*h |
| Mircera | AUC(0-672 Hour) | 89409.3 (mmol/L)*h |
Secondary
AUEC(0-672 Hour)
Area under the effect curve from the drug injection to 672 h \[28 days\]) based on the change in the absolute reticulocyte count after the first injection of the test/reference drug
Time frame: 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | AUEC(0-672 Hour) | 7210.479 (cells*10^9)*h | Standard Deviation 5465.155 |
| BCD-131 1,7 mcg/kg * Conversion Ratio | AUEC(0-672 Hour) | 11274.380 (cells*10^9)*h | Standard Deviation 12460.177 |
| Mircera | AUEC(0-672 Hour) | 12131.820 (cells*10^9)*h | Standard Deviation 15613.087 |
Secondary
Cmax
Maximum serum concentration of the drug product) after the first injection of the test/reference drug
Time frame: 3, 6, 12, 24, 48, 72, 96, 168, 336, 504, 672 h h after injection 1, weeks 5, 9, 13, 17, 21
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | Cmax | 195.3 mmol/L |
| BCD-131 1,7 mcg/kg * Conversion Ratio | Cmax | 231.9 mmol/L |
| Mircera | Cmax | 617.6 mmol/L |
Secondary
The Proportion of BAb- and NAb-positive Patients
Blood sampling for immunogenicity assessment (BAbs and NAbs) will be performed in all the patients included in the study before the first injection and then at Week 9 and Week 23. The immunogenicity endpoints will be analyzed after the completion of all periods of the study.
Time frame: Week 9, 23
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | The Proportion of BAb- and NAb-positive Patients | 0 Participants |
| BCD-131 1,7 mcg/kg * Conversion Ratio | The Proportion of BAb- and NAb-positive Patients | 0 Participants |
| Mircera | The Proportion of BAb- and NAb-positive Patients | 0 Participants |
Secondary
The Proportion of Patients Who Developed AEs/SAEs That, in the Investigator's Opinion, Are Related to BCD-131
The proportion of patients, in each group, who developed СТСАЕ v. 4.03 Grade 3-4 AEs that, in the Investigator's opinion, are related to BCD-131 \- the proportion of patients, in each group, who discontinued the study due to AEs/SAEs
Time frame: Week 23
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-131 1,05 mcg/kg * Conversion Ratio | The Proportion of Patients Who Developed AEs/SAEs That, in the Investigator's Opinion, Are Related to BCD-131 | 5 Participants |
| BCD-131 1,7 mcg/kg * Conversion Ratio | The Proportion of Patients Who Developed AEs/SAEs That, in the Investigator's Opinion, Are Related to BCD-131 | 2 Participants |
| Mircera | The Proportion of Patients Who Developed AEs/SAEs That, in the Investigator's Opinion, Are Related to BCD-131 | 2 Participants |