Anemia
Conditions
Keywords
Treatment of anemia in hemodialysis patients
Brief summary
This is a double-blind, randomized, multicenter, parallel-group, equivalence study involving about 462 clinically stable hemodialysis patients aged 18 years or above suffering from anemia and treated previously with a stable dose of ERYPO® intravenously.
Detailed description
The primary objective of this Phase III study is the evaluation of therapeutic equivalence of HX575 Hexal AG and a comparator of epoetin alfa, ERYPO® in the maintenance intravenous treatment of renal anemia. Efficacy, dosage and safety of HX575 Hexal AG in the long-term treatment were assessed.
Interventions
DRUGHX575 epoetin alfa Hexal AG
HX575 Solution for i.v. injection Containing 1000, 2000 and 4000 IU of rh erythropoietin
DRUGERYPO®, Janssen-Cilag
Solution for i.v. injection
Sponsors
Hexal AG
Sandoz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving dialysis for at least 6 months (3 times weekly) before screening * Age: \>=18 * Clinically stable, i.e. hemoglobin within the established range (10.0 to 13.0 g/dl) for at least 12 weeks before screening * Stable intravenous dosage of ERYPO® three times weekly for at least 8 weeks before screening and during screening with a maximal weekly dosage of 300 IU/kg body weight (stable is defined as \<25% change (up or down) in weekly dose and no change in frequency over 8 weeks prior screening and 10 weeks prior randomisation) * Baseline hemoglobin concentration of 10.0 to 13.0 g/dl (mean of two pre-randomization pre-dialysis samples of Hb at visit -2 and visit 1) * Serum ferritin \>=100 µg/l and/or saturated transferrin levels \>=20% * C-reactive protein \<15 mg/l (\< 5 mg/l: normal; \>= 5 mg/l \< 10 mg/l: +; \>=10mg/l \< 100 mg/l: ++; \>=100 mg/l: +++) * Ability to follow study instructions and likely to complete all required visits * Written informed consent of the patient
Exclusion criteria
* Anemia of non-renal causes * Primary hematologic disorder (e.g. myelodysplastic syndrome, sickle cell anemia, hematological malignancy, hemolytic anemia) * Evidence of severe hepatic dysfunction (ALT and/or AST above 2 x upper limit of normal range; or gamma-GT above 3 x upper limit of normal range) * Clinical evidence of current uncontrolled hyperparathyroidism (serum parathyroid hormone \>1500 pg/mL). * Known history of bone marrow disease * Any red blood cell transfusion(s) during the last 12 weeks before screening or during the screening/baseline period * Insufficient concomitant iron treatment during the last 2 months before Visit -2 * Uncontrolled hypertension, defined as a predialysis diastolic blood pressure measurement \>=110 mmHg during the screening period * Congestive heart failure \[New York Heart Association (NYHA) class III and IV\] * Unstable angina pectoris, active cardiac disease, cardiac infarction during the last six months before screening * History of blood coagulation disease * Thrombocytopenia (platelet count \<100.000/µl) * Leukopenia (white blood cell count \< 2.000/µl) * Overt bleeding (acute or chronic bleeding within 2 months of inclusion) or hemolysis * Evidence of acute infectious disease or serious active inflammatory states within one months before screening (Visit -2) or during the screening/baseline period * Suspicion or known PRCA (pure red cell aplasia) * Previously diagnosed HIV or acute hepatitis infection * Treatment for epilepsy within the past 6 months * Planned surgery during the next 7 months (except vascular access surgery) * Any androgen therapy within 2 months before visit -2 and during the study * Therapy with immunosuppressants or any drug known to affect the hematocrit within 1 month before Visit -2 and during the study * Clinical evidence of malignant diseases * Pregnancy, breastfeeding women or women not using adequate birth control measures * Known history of severe drug related allergies * Known allergy to one of the ingredients of the test or reference products or hypersensitivity to mammalian-derived products * Simultaneous participation in another clinical study or participation in a study in the month preceding the start of this study or previously randomized in this study * Participation in an erythropoietin study in the 3 months preceding screening (visit -2) * Any other condition which at the investigator´s discretion may put the patient at risk or which may confound the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Compare the Efficacy of HX575 Hexal AG and ERYPO® Janssen-Cilag. | 28 weeks | Primary endpoint was the mean absolute change in Hb level between the screening/baseline and the evaluation period. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between epoetin alfa HX575 Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\]. Primary Endpoint was analyzed based on intent-to-treat (ITT) population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Absolute Change in Hemoglobin Level From the Screening/Baseline Period to the Evaluation Period - ITT Population | 28 weeks | The mean absolute change in Hb levels between the screening/baseline period and the evaluation period was analyzed for the intent-to-treat (ITT) population in the same way as the primary efficacy endpoint. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between HX575 epoetin alfa Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\]. |
Countries
Austria, Germany
Participant flow
Recruitment details
A total of 568 patients were screened. 479 were eligible for inclusion and were randomized. 478 patients were started on treatment with either epoetin alfa HX575 Hexal AG or ERYPO®, Janssen-Cilag. As the randomization followed a 2:1 scheme, 314 patients received HX575 Hexal AG and 164 patients received ERYPO®.
Pre-assignment details
The first part of the study was designed as a double-blind, randomized, multicenter, parallel-group equivalence study and consisted of two phases: Phase I (dose adjustment and maintenance of Hb level; until week 24) followed by Phase II (evaluation period: four week evaluation period to determine the primary efficacy endpoint; weeks 25 until 28).
Participants by arm
| Arm | Count |
|---|---|
| HX575 Epoetin Alfa Hexal AG Eligible patients were switched from the comparator to HX575 epoetin alfa Hexal AG in ratio 2:1. Treatment was done intravenously (solution for injection i.v.) in pre-filled syringes for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28. | 314 |
| ERYPO®, Janssen-Cilag Eligible patients were randomized and continued to be treated with ERYPO® Janssen-Cilag intravenously in pre-filled syringes (solution for injection i.v.) for 24 weeks. The maximum weekly dose was 300 UI/kg body weight (given 1 to 3 times) to maintain hemoglobin levels between 10-13 g/dL. Baseline HB value after 24 weeks was required for efficacy analysis at week 28. | 164 |
| Total | 478 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 |
| Overall Study | Death | 15 | 4 |
| Overall Study | Hemoglobulin concentration | 4 | 3 |
| Overall Study | Incl./excl. not fulfilled | 7 | 2 |
| Overall Study | Kidney Transplantation (NTX) | 10 | 2 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Planned operation | 2 | 0 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 2 |
Baseline characteristics
| Characteristic | HX575 Epoetin Alfa Hexal AG | ERYPO®, Janssen-Cilag | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 169 Participants | 80 Participants | 249 Participants |
| Age, Categorical Between 18 and 65 years | 145 Participants | 84 Participants | 229 Participants |
| Age, Continuous | 62.3 years STANDARD_DEVIATION 14.4 | 62.6 years STANDARD_DEVIATION 13.8 | 62.4 years STANDARD_DEVIATION 14.2 |
| Body weight | 76.3 kg STANDARD_DEVIATION 15.5 | 76.0 kg STANDARD_DEVIATION 17.7 | 76.2 kg STANDARD_DEVIATION 16.2 |
| Region of Enrollment Austria | 70 participants | 37 participants | 107 participants |
| Region of Enrollment Germany | 244 participants | 127 participants | 371 participants |
| Sex: Female, Male Female | 138 Participants | 98 Participants | 236 Participants |
| Sex: Female, Male Male | 176 Participants | 66 Participants | 242 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 19 / 314 | 5 / 164 |
| other Total, other adverse events | 283 / 314 | 154 / 164 |
| serious Total, serious adverse events | 112 / 314 | 57 / 164 |
Outcome results
Primary
To Compare the Efficacy of HX575 Hexal AG and ERYPO® Janssen-Cilag.
Primary endpoint was the mean absolute change in Hb level between the screening/baseline and the evaluation period. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between epoetin alfa HX575 Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\]. Primary Endpoint was analyzed based on intent-to-treat (ITT) population.
Time frame: 28 weeks
Population: Primary Endpoint was analyzed based on ITT population: all treated patients with a post baseline hemoglobin value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| HX575 Epoetin Alfa Hexal AG | To Compare the Efficacy of HX575 Hexal AG and ERYPO® Janssen-Cilag. | 0.147 g/dL | Standard Error 0.092 |
| ERYPO®, Janssen-Cilag | To Compare the Efficacy of HX575 Hexal AG and ERYPO® Janssen-Cilag. | 0.063 g/dL | Standard Error 0.117 |
95% CI: [-0.17, 0.338]
Secondary
Mean Absolute Change in Hemoglobin Level From the Screening/Baseline Period to the Evaluation Period - ITT Population
The mean absolute change in Hb levels between the screening/baseline period and the evaluation period was analyzed for the intent-to-treat (ITT) population in the same way as the primary efficacy endpoint. A two-sided 95 % confidence interval for the difference in mean change (mean of evaluation period - mean of screening/baseline period) in Hb between HX575 epoetin alfa Hexal AG and ERYPO® Janssen-Cilag was computed. The difference was estimated from an analysis of a co-variance model including factors treatment, center, mean baseline Hb (\<11.5 and ≥11.5 g/dL) as factors and change of the mean weekly dose from screening/baseline to the evaluation period (of HX575 epoetin alfa Hexal AG or ERYPO® Janssen-Cilag) as a covariate. HX575 Hexal AG was considered at least as good as ERYPO® Janssen-Cilag if the 95 % confidence interval of the difference in mean changes in Hb levels between HX575 Hexal AG and ERYPO® Janssen-Cilag lied entirely within the interval \[-0.5 g/dL; 0.5 g/dL\].
Time frame: 28 weeks
Population: Intent-to-treat population (ITT): all randomized patients who received at least one dose of the study medication and for whom at least one post-baseline value of the primary endpoint Hb was available. A prerequisite to be included in the ITT population was that they were treated for four weeks with Hb values available during this period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| HX575 Epoetin Alfa Hexal AG | Mean Absolute Change in Hemoglobin Level From the Screening/Baseline Period to the Evaluation Period - ITT Population | 0.003 g/dL | Standard Error 0.079 |
| ERYPO®, Janssen-Cilag | Mean Absolute Change in Hemoglobin Level From the Screening/Baseline Period to the Evaluation Period - ITT Population | -0.187 g/dL | Standard Error 0.105 |
95% CI: [-0.039, 0.418]