Anemia, Chronic Kidney Disease, End Stage Renal Failure on Dialysis
Conditions
Keywords
darbepoetin alfa
Brief summary
The purpose of the study is to prove equivalence of efficacy and safety of BCD-066 and Aranesp® in treatment of anemia in end-stage chronic kidney disease patients on dialysis.
Detailed description
In this study CKD patients on dialysis previously treated by short-acting epoetins will switch to one of darbepoetin alfa products - BCD-066 (experimental arm) or Aranesp (active comparator) to maintain previously achieved target level of hemoglobin (100-120 g/l). Patients will be treated for 52 weeks. IV iron supplementation will be provided to maintain serum ferritin level above 500 µg/l according to KDIGO Anemia Guidelines (2012).
Interventions
DRUGDarbepoetin alfa
Weekly sc administration of darbepoetin alfa
Sponsors
Biocad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Age between 18 and 75 years * End-stage kidney disease * Need for dialysis for at least 3 months before enrollment * Need for at least 12 hours on standard dialysis procedure weekly * Regular rHuEpo (epoetin alfa, epoetin beta, darbepoetin alfa) administration 1, 2 or 3 times a week (stable dose, stable frequency) for at least 3 months before enrollment * Target hemoglobin level (100-120 g/l) for at least 3 months before enrollment * Effective dialysis (Kt/v≥1,2) * 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 (according to Investigator's assessment)
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 * Hemoglobin above 120 g/l or below 100 g/l * Scheduled kidney transplant during study participation period * Binding/neutralizing antibodies against erythropoetin/darbepoetin * History of severe allergic reactions * Vaccination less than 8 weeks before enrollment * Liver cirrhosis with portal hypertension and/or splenomegaly and/or ascitis * HIV infection, active HBV, HCV * ALT, AST level above 3x ULN * Bone marrow fibrosis * Congestive heart failure (Grade IV NYHA) * Resistant arterial hypertension * Unstable angina * Hemoglobinopathy, MDS, hematologic malignancy * PRCA * Severe secondary hyperparathyroidism (PTH \> 9x ULN) * GI bleeding history * Thrombotic events history (myocardial infarction, stroke, TIA, DVT, PATE) less than 6 months before enrollment * Acute hemolysis history * Seizures, including epilepsy * Major surgery in less than 1 month before enrollment * Blood transfusions in less than 3 months before enrollment * Acute inflammatory diseases or exacerbations of chronic inflammation including septic of aseptic inflammation foci * Severe psychiatric disorders * History of malignancy, excluding appropriately treated basal cell carcinoma or cervical carcinoma in situ * Alcohol or drug abuse * Hypersensitivity to darbepoetin alfa of any components of study drugs * Simultaneous participation in other trials or in less than 3 months before enrollment * Pregnancy of breast-feeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 24 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Darbepoetin Alfa Dose During Evaluation Period | Week 21 to Week 24 | The outcome includes the mean weekly dose of Darbepoetin Alfa which was administered to the patients during the period from week 21 to week 24 (last 4 weeks of the main period of the study) |
| Number or Percentage of Patients With Need for Blood Transfusions | Weeks 1 to 24 | — |
| Number or Percentage of Patients With Need for 'Dose Titration' at the Beginning of the Study | Weeks 1 to 20 | — |
| Mean Hemoglobin Level During Evaluation Period | Week 24 | The outcome includes the mean hemoglobin level which was registered in the patients during the last 4 weeks of the main period of the study (period from week 21 to week 24) |
| Number or Percentage of Patients With Hemoglobin Level Between 90 and 100 g/l | Weeks 21 to 24 | — |
| Hemoglobin Level Dynamics | Weeks 1 to 24 | — |
| Mean Darbepoetin Alfa Dose During the Whole Study | Week 24 | The outcome includes the mean Darbepoetin Alfa Dose During the Whole Study |
| Number or Percentage of Patients Who Have Target Hemoglobin Concentration During Evaluation Period | Weeks 21 to 24 | Hb concentration between 100 and 120 g/l will be considered as target |
| Mean Hematocrit Level During the Whole Study | Week 24 | — |
| Number of Patients With AE/SAE (AE/SAE Incidence) | Weeks 1 to 52 | — |
| Number of Participants With Grade 3-4 AE/SAE | Weeks 1 to 52 | — |
| Number of Participants Who Withdrew From Study Due to AE/SAE | Weeks 1 to 52 | — |
| Number of Participants With Arterial and Venous Thrombotic Events | Weeks 1 to 52 | — |
| Number or Percentage of Patients With Binding and/or Neutralizing Antibodies Against Darbepoetin Alfa | Weeks 1 to 52 | — |
| Mean Hemoglobin Level During the Whole Study (24 Week) | Week 24 | The outcome includes the measuere of Mean Hemoglobin Level During the Whole Study (during the study period from week 1 to week 24 week) |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BCD-066 Patients in this arm received weekly subcutaneous injections of BCD-066 (darbepoetin alfa) with dose level titration to maintain target hemoglobin level (100 - 120 g/l) for 52 weeks
Darbepoetin alfa: weekly sc administration of darbepoetin alfa | 98 |
| Aranesp Patients in this arm received weekly subcutaneous injections of Aranesp (darbepoetin alfa) with dose level titration to maintain target hemoglobin level (100 - 120 g/l) for 52 weeks
Darbepoetin alfa: weekly sc administration of darbepoetin alfa | 97 |
| Total | 195 |
Baseline characteristics
| Characteristic | Total | BCD-066 | Aranesp |
|---|---|---|---|
| Age, Continuous mITT population | 57 years | 58 years | 56 years |
| Age, Continuous Per protocol | 56.5 years | 57.5 years | 56 years |
| Race (NIH/OMB) mITT American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) mITT Asian | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) mITT Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) mITT More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) mITT Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) mITT Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) mITT White | 191 Participants | 95 Participants | 96 Participants |
| Race (NIH/OMB) Per protocol American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per protocol Asian | 4 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Per protocol Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per protocol More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per protocol Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per protocol Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Per protocol White | 172 Participants | 83 Participants | 89 Participants |
| Sex: Female, Male mITT Female | 99 Participants | 56 Participants | 43 Participants |
| Sex: Female, Male mITT Male | 96 Participants | 42 Participants | 54 Participants |
| Sex: Female, Male Per protocol Female | 87 Participants | 47 Participants | 40 Participants |
| Sex: Female, Male Per protocol Male | 89 Participants | 39 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 98 | 4 / 97 |
| other Total, other adverse events | 84 / 98 | 84 / 97 |
| serious Total, serious adverse events | 19 / 98 | 13 / 97 |
Outcome results
Primary
Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period
Time frame: Baseline - measurements on Screening (weeks -4 - 0) and on day 1; Evaluation period - weekly measures on weeks 21 to 24
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | 4.695 gram per liter | Standard Deviation 10.941 |
| Aranesp | Change in Hemoglobin (Hb) Concentration From Baseline to the Evaluation Period | 4.641 gram per liter | Standard Deviation 8.987 |
Secondary
Hemoglobin Level Dynamics
Time frame: Weeks 1 to 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BCD-066 | Hemoglobin Level Dynamics | Week 1 | 111.155 gram per liter | Standard Deviation 8.713 |
| BCD-066 | Hemoglobin Level Dynamics | Week 2 | 111.831 gram per liter | Standard Deviation 9.332 |
| BCD-066 | Hemoglobin Level Dynamics | Week 3 | 113.802 gram per liter | Standard Deviation 8.962 |
| BCD-066 | Hemoglobin Level Dynamics | Week 4 | 114.686 gram per liter | Standard Deviation 9.416 |
| BCD-066 | Hemoglobin Level Dynamics | Week 8 | 116.279 gram per liter | Standard Deviation 10.327 |
| BCD-066 | Hemoglobin Level Dynamics | Week 12 | 117.520 gram per liter | Standard Deviation 10.317 |
| BCD-066 | Hemoglobin Level Dynamics | Week 16 | 117.326 gram per liter | Standard Deviation 11.646 |
| BCD-066 | Hemoglobin Level Dynamics | Week 20 | 113.80 gram per liter | Standard Deviation 10.61 |
| BCD-066 | Hemoglobin Level Dynamics | Week 21 | 114.593 gram per liter | Standard Deviation 10.951 |
| BCD-066 | Hemoglobin Level Dynamics | Week 22 | 114.372 gram per liter | Standard Deviation 10.619 |
| BCD-066 | Hemoglobin Level Dynamics | Week 23 | 114.247 gram per liter | Standard Deviation 9.645 |
| BCD-066 | Hemoglobin Level Dynamics | Week 24 | 113.174 gram per liter | Standard Deviation 9.604 |
| Aranesp | Hemoglobin Level Dynamics | Week 23 | 114.582 gram per liter | Standard Deviation 9.143 |
| Aranesp | Hemoglobin Level Dynamics | Week 1 | 112.68 gram per liter | Standard Deviation 8.827 |
| Aranesp | Hemoglobin Level Dynamics | Week 16 | 115.322 gram per liter | Standard Deviation 9.419 |
| Aranesp | Hemoglobin Level Dynamics | Week 2 | 113.619 gram per liter | Standard Deviation 9.85 |
| Aranesp | Hemoglobin Level Dynamics | Week 22 | 115.467 gram per liter | Standard Deviation 8.656 |
| Aranesp | Hemoglobin Level Dynamics | Week 3 | 115.378 gram per liter | Standard Deviation 9.541 |
| Aranesp | Hemoglobin Level Dynamics | Week 20 | 116.528 gram per liter | Standard Deviation 9.05 |
| Aranesp | Hemoglobin Level Dynamics | Week 4 | 116.533 gram per liter | Standard Deviation 10.276 |
| Aranesp | Hemoglobin Level Dynamics | Week 24 | 115.444 gram per liter | Standard Deviation 8.8 |
| Aranesp | Hemoglobin Level Dynamics | Week 8 | 116.846 gram per liter | Standard Deviation 9.589 |
| Aranesp | Hemoglobin Level Dynamics | Week 21 | 115.966 gram per liter | Standard Deviation 9.598 |
| Aranesp | Hemoglobin Level Dynamics | Week 12 | 116.878 gram per liter | Standard Deviation 10.488 |
Secondary
Mean Darbepoetin Alfa Dose During Evaluation Period
The outcome includes the mean weekly dose of Darbepoetin Alfa which was administered to the patients during the period from week 21 to week 24 (last 4 weeks of the main period of the study)
Time frame: Week 21 to Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Mean Darbepoetin Alfa Dose During Evaluation Period | 20.779 micrograms | Standard Deviation 10.858 |
| Aranesp | Mean Darbepoetin Alfa Dose During Evaluation Period | 20.982 micrograms | Standard Deviation 10.97 |
Secondary
Mean Darbepoetin Alfa Dose During the Whole Study
The outcome includes the mean Darbepoetin Alfa Dose During the Whole Study
Time frame: Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Mean Darbepoetin Alfa Dose During the Whole Study | 22.625 micrograms | Standard Deviation 10.637 |
| Aranesp | Mean Darbepoetin Alfa Dose During the Whole Study | 22.449 micrograms | Standard Deviation 11.541 |
Secondary
Mean Hematocrit Level During the Whole Study
Time frame: Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Mean Hematocrit Level During the Whole Study | 35.119 percentage of hematocrit (%) | Standard Deviation 2.194 |
| Aranesp | Mean Hematocrit Level During the Whole Study | 35.173 percentage of hematocrit (%) | Standard Deviation 2.502 |
Secondary
Mean Hemoglobin Level During Evaluation Period
The outcome includes the mean hemoglobin level which was registered in the patients during the last 4 weeks of the main period of the study (period from week 21 to week 24)
Time frame: Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Mean Hemoglobin Level During Evaluation Period | 114.054 gram per liter | Standard Deviation 9.222 |
| Aranesp | Mean Hemoglobin Level During Evaluation Period | 115.277 gram per liter | Standard Deviation 7.966 |
Secondary
Mean Hemoglobin Level During the Whole Study (24 Week)
The outcome includes the measuere of Mean Hemoglobin Level During the Whole Study (during the study period from week 1 to week 24 week)
Time frame: Week 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BCD-066 | Mean Hemoglobin Level During the Whole Study (24 Week) | 114.394 gram per liter | Standard Deviation 6.376 |
| Aranesp | Mean Hemoglobin Level During the Whole Study (24 Week) | 115.434 gram per liter | Standard Deviation 6.213 |
Secondary
Number of Participants Who Withdrew From Study Due to AE/SAE
Time frame: Weeks 1 to 52
Population: The analysis included all patients who received at least one injection of BCD-066 or Aranesp - mITT population.~One patient from Aranesp group was excluded prior to the first administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number of Participants Who Withdrew From Study Due to AE/SAE | 6 Participants |
| Aranesp | Number of Participants Who Withdrew From Study Due to AE/SAE | 4 Participants |
Secondary
Number of Participants With Arterial and Venous Thrombotic Events
Time frame: Weeks 1 to 52
Population: The analysis included all patients who received at least one injection of BCD-066 or Aranesp - mITT population.~One patient from Aranesp group was excluded prior to the first administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number of Participants With Arterial and Venous Thrombotic Events | 4 Participants |
| Aranesp | Number of Participants With Arterial and Venous Thrombotic Events | 5 Participants |
Secondary
Number of Participants With Grade 3-4 AE/SAE
Time frame: Weeks 1 to 52
Population: The analysis included all patients who received at least one injection of BCD-066 or Aranesp - mITT population.~One patient from Aranesp group was excluded prior to the first administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number of Participants With Grade 3-4 AE/SAE | 60 Participants |
| Aranesp | Number of Participants With Grade 3-4 AE/SAE | 51 Participants |
Secondary
Number of Patients With AE/SAE (AE/SAE Incidence)
Time frame: Weeks 1 to 52
Population: The analysis included all patients who received at least one injection of BCD-066 or Aranesp - mITT population.~One patient from Aranesp group was excluded prior to the first administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number of Patients With AE/SAE (AE/SAE Incidence) | 79 Participants |
| Aranesp | Number of Patients With AE/SAE (AE/SAE Incidence) | 76 Participants |
Secondary
Number or Percentage of Patients Who Have Target Hemoglobin Concentration During Evaluation Period
Hb concentration between 100 and 120 g/l will be considered as target
Time frame: Weeks 21 to 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number or Percentage of Patients Who Have Target Hemoglobin Concentration During Evaluation Period | 61 Participants |
| Aranesp | Number or Percentage of Patients Who Have Target Hemoglobin Concentration During Evaluation Period | 61 Participants |
Secondary
Number or Percentage of Patients With Binding and/or Neutralizing Antibodies Against Darbepoetin Alfa
Time frame: Weeks 1 to 52
Population: The analysis included all patients who received at least one injection of BCD-066 or Aranesp - mITT population.~One patient from Aranesp group was excluded prior to the first administration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number or Percentage of Patients With Binding and/or Neutralizing Antibodies Against Darbepoetin Alfa | 0 Participants |
| Aranesp | Number or Percentage of Patients With Binding and/or Neutralizing Antibodies Against Darbepoetin Alfa | 0 Participants |
Secondary
Number or Percentage of Patients With Hemoglobin Level Between 90 and 100 g/l
Time frame: Weeks 21 to 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number or Percentage of Patients With Hemoglobin Level Between 90 and 100 g/l | 1 Participants |
| Aranesp | Number or Percentage of Patients With Hemoglobin Level Between 90 and 100 g/l | 1 Participants |
Secondary
Number or Percentage of Patients With Need for Blood Transfusions
Time frame: Weeks 1 to 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number or Percentage of Patients With Need for Blood Transfusions | 0 Participants |
| Aranesp | Number or Percentage of Patients With Need for Blood Transfusions | 0 Participants |
Secondary
Number or Percentage of Patients With Need for 'Dose Titration' at the Beginning of the Study
Time frame: Weeks 1 to 20
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BCD-066 | Number or Percentage of Patients With Need for 'Dose Titration' at the Beginning of the Study | 31 Participants |
| Aranesp | Number or Percentage of Patients With Need for 'Dose Titration' at the Beginning of the Study | 24 Participants |