A Phase 2 Clinical Study of Pegerythropoietin Injection (RD01) for the Treatment of Anemia in Chronic Renal Failure Patients With Hemodialysis

Study Overview
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Brief Summary
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A multicenter randomized, single blind, active comparator controlled phase 2 study which is to evaluate the effectiveness, safety and the PK/PD characteristics of different doses, frequencies and routes of pegerythropoietin Injection (RD01) as maintenance therapy in the treatment of anemia in chronic renal failure patients with hemodialysis

Detailed Description
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This trial is a multicenter randomized, single blind, active comparator controlled phase 2 study. The study is divided into two stages. The first stage lasts for 18 weeks, and is divided into fixed dose period (day 1  6th week ) and dose adjustment period (7th   18th week). The second stage lasts for 28 weeks, and is also divided into dose adjustment period (19th   38th week) and evaluation period (39th   46th week). Patients are randomly assigned to seven study groups in the first stage. Of all these seven groups, six groups are: Group A (0.8μg/kg RD01, once every two weeks, subcutaneous injection, for 18 weeks)、Group B (1.2μg/kg RD01, once every two weeks, subcutaneous injection, for 18 weeks)、Group C (1.6μg/kg RD01, once every two weeks, subcutaneous injection, for 18 weeks)、 Group D (0.8ug/kg RD01, once every two weeks, intravenous injection, for 18 weeks)、Group E ( 150 IU/kg rHuEPO, once a week, subcutaneous injection, for 18 weeks )、Group F (8μl /kg placebo, once every two weeks, for 6 weeks; then 150 IU/kg rHuEPO, once a week, subcutaneous injection, 7th   18th week ). At the beginning of the second stage, some patients in these six goups need to be be randomized again. Of which patients in Group A、B、C are randomly assigned to Group a ( RD01, once every two weeks, subcutaneous injection, 19th   46th week )、Group b (RD01, once every four weeks, subcutaneous injection, 19th   46th week)、Group c (RD01, once every six weeks, subcutaneous injection, 19th   46th week); Patients in Group D enter directly to Group d (RD01, once every four weeks, intravenous injection, 19th   46th week); Patients in Group E and F are randomly assigned to Group e (rHuEPO once a week, intravenous injection, 19th   46th week ) and Group f (rHuEPO once a week, subcutaneous injection, 19th   46th week). The starting dose of the second stage for individual patient in all groups refers to the weekly dose at the end of the first stage . During the whole study period, all patients in six groups are not allowed to adjust dosage in the first 6 weeks, while in the remaining trial period dosage adjustment was allowed once every two weeks if necessary. There is a special Group G (1.6μg/kg RD01, once every four weeks, subcutaneous injection, Day 1   28th week), all patients are allowed to adjust dosage during the whole 28 weeks. This phase 2 study is to evaluate the effectiveness, safety and the PK/PD characteristics of different doses, frequencies and routes of pegerythropoietin Injection (RD01) as maintenance therapy in the treatment of anemia in chronic renal failure patients with hemodialysis

Official Title
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A Multicenter, Randomized, Single-blind, Active Comparator Controlled Phase 2 Clinical Study on the Effectiveness, Safety and Pharmacokinetics of Pegerythropoietin Injection (RD01) in Different Medication Schemes for the Treatment of Anemia in Chronic Renal Failure Patients With Hemodialysis

Conditions
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Patient of Anemia in Chronic Renal Failure With Hemodialysis

Intervention / Treatment
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* Drug: RD01
* Drug: Recombinant Human Erythropoiesis Injection (CHO cell)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic renal failure who are undergoing maintenance hemodialysis for at least 12 weeks; 18 ≤ age ≤ 75 years of age, male or female; Patients who have received short-acting EPO treatment and meets the treatment standard (hemoglobin 100   120 g / L). The mean Hb value in the screening period (at least two weeks apart ) is within the range of 100   120 g / L (both ends). The difference is less than 10g / L; Evaluation of iron status during the screening period, transferrin saturation (TSAT) ≥20% or serum ferritin (SF) ≥200 μg / L; Evaluation of dialysis adequacy during the screening period, with SpKt / V≥1.2 or URR≥65%; Subjects agree to use reliable contraceptives from the screening period to within 6 months after the last medication Sign the informed consent. Exclusion Criteria: Patients who have received or plan to have a kidney transplant during the study period Except of renal anemia, there are other diseases that cause chronic anemia (such as sickle cell anemia, myelodysplastic syndrome, hematological malignancies, myeloma, hemolytic anemia, pure red blood cell aplastic anemia) Patients with acute or chronic blood loss (such as upper gastrointestinal bleeding) in the past 3 months or patients who have undergone surgery with extensive bleeding, or patients who plan to undergo surgery during the study period Patients with coagulation dysfunction (time to activate partial thromboplastin> 1.5 times the upper limit of normal value) The following circumstances (including but not limited to) during the screening, investigators evaluated that it is not suitable for enrollment: Abnormal liver function (aspartate aminotransferase or alanine aminotransferase is more than 3 times the upper limit of normal value); Patients who were positive for Hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBeAg), HIV antibody (HIV-Ab), hepatitis C virus antibody (HCV-Ab) or Treponema pallidum antibody; Patients with severe secondary hyperparathyroidism (iPTH> 1000 ng / L); Patients with severe hypertension and poor control of blood pressure (systolic blood pressure> 180 mmHg or diastolic blood pressure> 100 mmHg) Patients with severe thromboembolic disease People with severe cardio-cerebral vascular disease (excluding luminal infarction), severe or unstable coronary artery disease, heart failure (NYHA III or IV) or myocardial infarction or stroke within 3 months Patients with malignant tumors (excluding non-melanoma skin cancer or resected cancer in situ) People with a history of severe allergies (including drug allergies), allergies to erythropoietin, or allergic to any component of the test drug (such as human serum albumin) People with severe infection who are receiving systemic antibiotics Patients who have received androgen therapy or blood transfusion therapy within the last 8 weeks; Participated in other new drug clinical trials as a subject within 3 months or the withdrawal time was shorter than the 5 half-life of the test drug at the time of enrollment (whichever is the longest); Patients with a history of seizures Pregnant and lactating women Alcohol, drug or drug addicts Other situations that the researcher believes may affect validity judgment or are not suitable for participation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group A +Group a<br>Group A: 0.8μg/kg RD01, once every two weeks, Day 1  18th week;Group a: refers to the weekly dose at the end of the first stage , once every two weeks, 19th 46th week | Drug: RD01<br>* RD01 is a PEGylated recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: pegerythropoietin Injection;|
| Experimental: Experimental Group B +Group b<br>Group B: 1.2μg/kg RD01, once every two weeks, Day 1  18th week; Group b: refers to the weekly dose at the end of the first stage , once every four weeks, 19th 46th week | Drug: RD01<br>* RD01 is a PEGylated recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: pegerythropoietin Injection;|
| Experimental: Experimental Group C +Group c<br>Group C: 1.6μg/kg RD01, once every two weeks, Day 1  18th week; Group c: refers to the weekly dose at the end of the first stage , once every six weeks, 19th 46th week | Drug: RD01<br>* RD01 is a PEGylated recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: pegerythropoietin Injection;|
| Experimental: Experimental Group D +Group d<br>Group D: 0.8μg/kg RD01, once every two weeks, Day 1  18th week; Group d: refers to the weekly dose at the end of the first stage , once every four weeks, 19th 46th week | Drug: RD01<br>* RD01 is a PEGylated recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: pegerythropoietin Injection;|
| Active Comparator: Experimental Group E +Group e<br>Group E: 150IU/kg rHuEPO, once a weeks, subcutaneous administration, Day 1  18th week; Group e: refers to the weekly dose at the end of the first stage , once a weeks, intravenous administration, 19th 46th week | Drug: Recombinant Human Erythropoiesis Injection (CHO cell)<br>* rHuEPO is a recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: rHuEPO;|
| Placebo Comparator: Experimental Group F +Group f<br>Group F: 8μl placebo, once every two weeks, for 6 weeks; 150 IU/kg rHuEPO, once week, subcutaneous injection, 7th   18th week; Group f: refers to the weekly dose at the end of the first stage , once a weeks, subcutaneous administration, 19th 46th week | Drug: Recombinant Human Erythropoiesis Injection (CHO cell)<br>* rHuEPO is a recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: rHuEPO;Drug: placebo<br>* placebo<br>|
| Experimental: Experimental Group G<br>Group G: 1.6μg/kg RD01, once every four weeks, Day 1  28th week; | Drug: RD01<br>* RD01 is a PEGylated recombinant human erythropoietin with the same biological effects as natural erythropoietin<br>* Other names: pegerythropoietin Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary efficacy index : The change of hemoglobin concentration of experimental group from baseline to the end of 4th and 6th week |  | Day 1 4th week & Day 1 6th week | 
| Primary efficacy index: The difference of hemoglobin concentration between the experimental group and the placebo group at the end of 4th and 6th week; |  | Day 1 4th week & Day 1 6th week | 
| Primary efficacy index: hemoglobin concentration change from baseline to the end of first stage | The amount of change in hemoglobin concentration from baseline to the end of the first stage | Day 1 18th week | 
| Primary efficacy index: hemoglobin concentration change from baseline to the evaluation periods in the second stage (39th  46th week) | The amount of change in hemoglobin concentration from baseline to the evaluation periods in the second stage (39th  46th week). | Day 1  evaluation periods (39th  46th week) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary efficacy index: the optimal dosage | The optimal dosage of the subjects at the end of the first stage and the evaluation period (39th  46th week) in the second stage | the end of 18th week & 39th  46th week | 
| Secondary efficacy index: maintenance rate | the proportion of subjects whose average Hb concentration remain within the target range during the evaluation period | 39th-46th week | 
| Secondary efficacy index : Proportion of subjects with unstable Hb during the evaluation period |  | 39th-46th week | 
| Secondary efficacy index: proportion of times of Hb remains within the target range | the proportion of times the measured Hb concentration remains within the target range during the evaluation period; | 39th-46th week | 
| Secondary efficacy index: EPO dose conversion coefficient of RD01 | EPO dose conversion factor for subjects at the end of the first stage and evaluation periods in the second stage | end of 18th week & 39th  46th week | 
| Safety indicator: adverse events | the type, proportion and severity of adverse events | for 46 weeks | 
| Immunogenicity indicator: incidence of anti-RD01 antibodies | incidence of anti-RD01 antibodies | for 46 weeks | 
| Maximum Plasma Concentration (Cmax) | the Cmax of RD01 in patients with long-term medication. | for 46 weeks | 
| Area Under the Curve (AUC) | the AUC of RD01 in patients with long-term medication. | for 46 weeks |