Anemia of Chronic Kidney Disease
Conditions
Keywords
epoetin, erythropoietin, Eprex, Hemax, Anemia, Chronic Kidney Disease, pre-dialysis
Brief summary
Phase III, multicenter, randomized, open, controlled clinical trial. A study designed as phase III, in 120 patients with chronic renal failure in the pre-dialysis stage, evaluate efficacy and safety of Hemax PFS® (PFS: prefilled syringes) vs the innovator erythropoietin alfa product (Eprex®).
Detailed description
This was a Phase IIIB, multicenter, randomized, open-label study to compare two products with epoetin alfa (HEMAX® PFS versus EPREX/ERYPO®). This trial was open-label for both the patient and the investigator, but blinded in the performance of laboratory analyses. The overall objective of the study was to evaluate the efficacy and the safety of HEMAX® PFS compared to EPREX/ERYPO®, following a dose-titration and maintenance scheme similar to the one used in the regular clinical practice. All patients received HEMAX® PFS or EPREX/ERYPO® twice a week subcutaneously during 12 weeks of titration, switching then to an equivalent weekly dose during 12 additional maintenance weeks. During the dosing scheme switch from twice a week to once weekly, each patient continued receiving the treatment assigned at randomization. The study conclude with n=43 patients.
Interventions
BIOLOGICALErythropoietin alfa
Prefilled syringes of erythropoietin
Sponsors
Bio Sidus SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Patients older than 18 years * Patients with pre-dialysis chronic renal failure (CRF) defined by a glomerular filtration rate (calculated with the Modification of Diet in Renal Disease Study formula) ≥15 ml/ min and \<60 ml/ min, by 1.73 m2 * Anemic patients that should be treated and levels of hemoglobin \<10.5 g/dl and ≥ 7.5 g/dl. * Patients that have the will and capacity to sign a written inform consent. * Post-menopause women for at least 2 years, or sterile by surgery for at least 6 months. Women of childbearing age must have a negative pregnancy test at baseline and be willing to get an adequate method of contraception.
Exclusion criteria
* Patients that are planned to be on dialysis or have a renal transplant in the following 6 months. * Transferrin iron Saturation \< 20%. * Etiology of renal failure (as secondary to autoimmune diseases) that, to the judge to the physician, can affect the normal development of the protocol. * Active bleeding or history of hemorrhage that have led to a significative decrease of hematocrit in the last 30 days. * Non-controlled hypertension (≥160 mm Hg of systolic pressure and/or ≥100 mm Hg of diastolic pressure with anti-hypertensive treatment). * Anemia caused by any other cause than renal disease. * Having a transfusion in the last 3 months before basal visit or during screening. * Treatment with an erythropoiesis stimulant in the last 3 months before basal visit or screening. * Increase risk of thromboembolic disease: history of arterial thromboembolia (stroke, transient ischemic attack, Acute coronary syndrome, etc.) in the last 6 months or venous in the last 12 months before screening; surgery in the last month before screening; prolong immobilization or orthopedic surgery programmed in the following 6 months or any other condition that to the judge of the investigator can increase the risk of thromboembolism. * Hematological disease or myelodysplastic syndrome or history of hematological neoplasm or solid tumor in the last 5 years. * History of congestive heart failure * Pregnancy or breast feeding * Refuse to participate in the protocol or any medical condition, that in the investigator opinion, is significant to prevent the participant from being included in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy Evaluation Through Change in Hemoglobin Levels | 12 weeks of treatment | Evaluate the efficacy of treatment with erythropoietin alfa through the measured changes in levels of hemoglobin from baseline value to the mean value of the 8 to 12 weeks of treatment, comparing patients treated with HEMAX® PFS versus EPREX/ ERYPO®. |
| Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24. | 24 weeks of treatment | Evaluate the safety through the incidence of adverse events and adverse reactions asessed after 12 and 24 weeks of treatment (week 24 reported which includes those evaluated at week 12), comparing patients treated with HEMAX® PFS versus those treated with EPREX/ ERYPO®. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change of Hemoglobin Level at Week 12 of Treatment | Intragroup efficacy until week 12 | Evaluate the efficacy between arms (HEMAX® PFS and EPREX/ ERYPO®) of treatment with erythropoietin alfa through the change in the level of hemoglobin from baseline in every visit until the week 12 visit. |
| Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Intragroup efficacy until week 24 | Evaluate the efficacy between arms (HEMAX® PFS and EPREX/ ERYPO®) of the change from the twice - a - week doses in the titration phase to a weekly dose in the maintenance phase through the changes in the hemoglobin levels from week 12 to weeks 16, 20 and 24 of treatment |
| Percentage of Responder Patients | 12 weeks of treatment | Evaluate the efficacy of treatment with erythropoietin alfa through the percentage of responder patients (increase of Hb ≥ 1g/ dl) after 12 weeks of treatment, comparing patients treated with HEMAX® PFS versus those treated with EPREX/ ERYPO®. |
| Concentration of Hepcidin | 24 weeks of treatment | Hepcidin will be analyzed by ELISA at baseline, week 12 and 24 in order to evaluate the treatment response. |
| Incidence of Anti-drug Antibodies (Immunogenicity) | 12 and 24 weeks of treatment | An anti-erythropoietin alfa antibody determination will be performed to evaluate treatment immunogenicity at week 12 and 24 visit |
| Percentage of Patients That Required Any Transfusion | 12 weeks of treatment | Evaluate the percentage of transfusional requirements after 12 weeks of treatment, comparing patients treated with HEMAX PFS versus those treated with EPREX/ ERYPO®. |
Countries
Argentina, Paraguay
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Eprex/Erypo Receive EPREX/ ERYPO® subcutaneously with an initial dose of 29 IU/ kg twice a week (2000 IU twice a week for 70 kg of weight), to be titrated according to the scheme that is summarized below.
There will be a follow - up of patients with visits to the site every two weeks during the first 12 weeks of dose titration that will be followed by 12 additional weeks of dose maintenance with visits every 4 weeks.
Erythropoietin alfa: Prefilled syringes of erythropoietin | 20 |
| Hemax PFS Receive HEMAX® PFS subcutaneously with an initial dose of 29 IU/ kg twice a week (2000 IU twice a week for 70 kg of weight), to be titrated according to the scheme that is summarized below.
There will be a follow - up of patients with visits to the site every two weeks during the first 12 weeks of dose titration that will be followed by 12 additional weeks of dose maintenance with visits every 4 weeks.
Erythropoietin alfa: Prefilled syringes of erythropoietin | 23 |
| Total | 43 |
Baseline characteristics
| Characteristic | Eprex/Erypo | Hemax PFS | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 23 Participants | 43 Participants |
| Age, Continuous | 60.5 years | 64 years | 61 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 23 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin blood level | 9.56 g/dL STANDARD_DEVIATION 0.6 | 9.44 g/dL STANDARD_DEVIATION 0.81 | 9.50 g/dL STANDARD_DEVIATION 0.72 |
| Region of Enrollment Argentina | 17 participants | 22 participants | 39 participants |
| Region of Enrollment Paraguay | 3 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 15 Participants | 17 Participants | 32 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 0 / 23 |
| other Total, other adverse events | 8 / 20 | 5 / 23 |
| serious Total, serious adverse events | 4 / 20 | 3 / 23 |
Outcome results
Primary
Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24.
Evaluate the safety through the incidence of adverse events and adverse reactions asessed after 12 and 24 weeks of treatment (week 24 reported which includes those evaluated at week 12), comparing patients treated with HEMAX® PFS versus those treated with EPREX/ ERYPO®.
Time frame: 24 weeks of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eprex/Erypo | Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24. | Overall Adverse Events | 23 Adverse Events |
| Eprex/Erypo | Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24. | Serious Events | 4 Adverse Events |
| Hemax PFS | Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24. | Overall Adverse Events | 30 Adverse Events |
| Hemax PFS | Adverse Events and Adverse Reactions (Safety and Tolerability) at Weeks 12 and 24. | Serious Events | 4 Adverse Events |
Primary
Efficacy Evaluation Through Change in Hemoglobin Levels
Evaluate the efficacy of treatment with erythropoietin alfa through the measured changes in levels of hemoglobin from baseline value to the mean value of the 8 to 12 weeks of treatment, comparing patients treated with HEMAX® PFS versus EPREX/ ERYPO®.
Time frame: 12 weeks of treatment
Population: Per protocol analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eprex/Erypo | Efficacy Evaluation Through Change in Hemoglobin Levels | Baseline hemoglobin levels | 9.56 Hemoglobin levels (g/dL) | Standard Deviation 0.6 |
| Eprex/Erypo | Efficacy Evaluation Through Change in Hemoglobin Levels | Average hemoglobin levels between visits 8 and 12 | 11.05 Hemoglobin levels (g/dL) | Standard Deviation 0.74 |
| Eprex/Erypo | Efficacy Evaluation Through Change in Hemoglobin Levels | Hemoglobin levels change between both times | 1.49 Hemoglobin levels (g/dL) | Standard Deviation 0.99 |
| Hemax PFS | Efficacy Evaluation Through Change in Hemoglobin Levels | Baseline hemoglobin levels | 9.44 Hemoglobin levels (g/dL) | Standard Deviation 0.81 |
| Hemax PFS | Efficacy Evaluation Through Change in Hemoglobin Levels | Average hemoglobin levels between visits 8 and 12 | 11.11 Hemoglobin levels (g/dL) | Standard Deviation 1.11 |
| Hemax PFS | Efficacy Evaluation Through Change in Hemoglobin Levels | Hemoglobin levels change between both times | 1.66 Hemoglobin levels (g/dL) | Standard Deviation 1.05 |
Secondary
Change of Hemoglobin Level at Week 12 of Treatment
Evaluate the efficacy between arms (HEMAX® PFS and EPREX/ ERYPO®) of treatment with erythropoietin alfa through the change in the level of hemoglobin from baseline in every visit until the week 12 visit.
Time frame: Intragroup efficacy until week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eprex/Erypo | Change of Hemoglobin Level at Week 12 of Treatment | Baseline | 9.56 Hemoglobin levels (g/dL) | Standard Deviation 0.6 |
| Eprex/Erypo | Change of Hemoglobin Level at Week 12 of Treatment | Change | 1.49 Hemoglobin levels (g/dL) | Standard Deviation 0.99 |
| Eprex/Erypo | Change of Hemoglobin Level at Week 12 of Treatment | Week 8 to 12 | 11.05 Hemoglobin levels (g/dL) | Standard Deviation 0.74 |
| Hemax PFS | Change of Hemoglobin Level at Week 12 of Treatment | Week 8 to 12 | 11.11 Hemoglobin levels (g/dL) | Standard Deviation 1.11 |
| Hemax PFS | Change of Hemoglobin Level at Week 12 of Treatment | Change | 1.66 Hemoglobin levels (g/dL) | Standard Deviation 1.05 |
| Hemax PFS | Change of Hemoglobin Level at Week 12 of Treatment | Baseline | 9.44 Hemoglobin levels (g/dL) | Standard Deviation 0.81 |
Secondary
Concentration of Hepcidin
Hepcidin will be analyzed by ELISA at baseline, week 12 and 24 in order to evaluate the treatment response.
Time frame: 24 weeks of treatment
Population: The analysis was restricted to patients with available hepcidin samples at baseline, 12 weeks, and 24 weeks due to an unanticipated loss of samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eprex/Erypo | Concentration of Hepcidin | Baseline | 84.80 ng hepcidin/ml | Standard Deviation 67.67 |
| Eprex/Erypo | Concentration of Hepcidin | Week 12 | 107.80 ng hepcidin/ml | Standard Deviation 96.31 |
| Eprex/Erypo | Concentration of Hepcidin | Week 24 | 83.60 ng hepcidin/ml | Standard Deviation 58.29 |
| Hemax PFS | Concentration of Hepcidin | Baseline | 74.21 ng hepcidin/ml | Standard Deviation 64.26 |
| Hemax PFS | Concentration of Hepcidin | Week 12 | 56.07 ng hepcidin/ml | Standard Deviation 55.62 |
| Hemax PFS | Concentration of Hepcidin | Week 24 | 60.93 ng hepcidin/ml | Standard Deviation 44.16 |
Secondary
Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration
Evaluate the efficacy between arms (HEMAX® PFS and EPREX/ ERYPO®) of the change from the twice - a - week doses in the titration phase to a weekly dose in the maintenance phase through the changes in the hemoglobin levels from week 12 to weeks 16, 20 and 24 of treatment
Time frame: Intragroup efficacy until week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Eprex/Erypo | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 12 | 11.08 Hemoglobin levels (g/dL) | Standard Deviation 0.9 |
| Eprex/Erypo | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 16 | 10.9 Hemoglobin levels (g/dL) | Standard Deviation 0.97 |
| Eprex/Erypo | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 20 | 10.51 Hemoglobin levels (g/dL) | Standard Deviation 0.9 |
| Eprex/Erypo | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 24 | 10.97 Hemoglobin levels (g/dL) | Standard Deviation 0.96 |
| Hemax PFS | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 24 | 10.85 Hemoglobin levels (g/dL) | Standard Deviation 1.44 |
| Hemax PFS | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 12 | 11.16 Hemoglobin levels (g/dL) | Standard Deviation 0.8 |
| Hemax PFS | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 20 | 10.71 Hemoglobin levels (g/dL) | Standard Deviation 1.09 |
| Hemax PFS | Evaluate the Efficacy Between Arms 24 Weeks: Week Doses in the Titration | Week 16 | 10.82 Hemoglobin levels (g/dL) | Standard Deviation 1.12 |
Secondary
Incidence of Anti-drug Antibodies (Immunogenicity)
An anti-erythropoietin alfa antibody determination will be performed to evaluate treatment immunogenicity at week 12 and 24 visit
Time frame: 12 and 24 weeks of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eprex/Erypo | Incidence of Anti-drug Antibodies (Immunogenicity) | Week 12 | 0 Participants with positive result |
| Eprex/Erypo | Incidence of Anti-drug Antibodies (Immunogenicity) | Week 24 | 0 Participants with positive result |
| Hemax PFS | Incidence of Anti-drug Antibodies (Immunogenicity) | Week 12 | 0 Participants with positive result |
| Hemax PFS | Incidence of Anti-drug Antibodies (Immunogenicity) | Week 24 | 1 Participants with positive result |
Secondary
Percentage of Patients That Required Any Transfusion
Evaluate the percentage of transfusional requirements after 12 weeks of treatment, comparing patients treated with HEMAX PFS versus those treated with EPREX/ ERYPO®.
Time frame: 12 weeks of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Eprex/Erypo | Percentage of Patients That Required Any Transfusion | 5 Percentage of patients |
| Hemax PFS | Percentage of Patients That Required Any Transfusion | 0 Percentage of patients |
Secondary
Percentage of Responder Patients
Evaluate the efficacy of treatment with erythropoietin alfa through the percentage of responder patients (increase of Hb ≥ 1g/ dl) after 12 weeks of treatment, comparing patients treated with HEMAX® PFS versus those treated with EPREX/ ERYPO®.
Time frame: 12 weeks of treatment
Population: Patients were classified as non-responders when hemoglobin did not increase at least 1 g/dL regarding baseline during any of the first 12 weeks of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Eprex/Erypo | Percentage of Responder Patients | Non-Responders | 5.56 percentage of participants |
| Eprex/Erypo | Percentage of Responder Patients | Responders | 94.44 percentage of participants |
| Hemax PFS | Percentage of Responder Patients | Non-Responders | 4.55 percentage of participants |
| Hemax PFS | Percentage of Responder Patients | Responders | 95.45 percentage of participants |