A Study of PEG-EPO Injection (CHO Cells) for Maintenance Therapy of Patients With Renal Anemia .

Study Overview
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Brief Summary
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The purpose of the study is to explore the optimal dose and administration of the experimental drug, and to evaluate the safety and efficacy of the drug in patients with renal anemia. Patients with renal anemia on regular dialysis treatment are expected to be enrolled in this study.

Detailed Description
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This study is a multi-center, randomized, open-label, positive controlled phase II clinical study. A total of 125 to 150 patients with renal anemia receiving regular dialysis were enrolled in this study. Those patients were randomly allocated to 5 treatment groups in a ratio of 1:1:1:1:1, with 25 to 30 patients in each group.

Official Title
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A Phase Ⅱ Clinical Study on the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Polyethylene Glycol Recombinant Human Erythropoietin Injection (CHO Cell) in Optimal Dose and Administration Regimen for Maintenance Therapy in Patients With Regular Dialysis Renal Anemia.

Conditions
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Renal Anemia

Intervention / Treatment
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* Biological: Recombinant human erythropoietin injection
* Biological: Human erythropoietin injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients at the age of 18 75 (including critical value). Patients clinically diagnosed with renal anemia who have received dialysis for at least 12 weeks (hemodialysis≥3 times/week, total urea clearance index (Kt/V) ≥1.2 or urea reduction rate (URR) ≥65%; peritoneal dialysis≥4 times/day, weekly Kt/V≥1.7); Hb in screening period should be within the range of 100 130g/L (including both ends), and the deviation should not exceed 10g/L; Iron status (TSAT ≥20% or SF ferritin ≥100μg/L) during screening. Have been stably treated with short-acting EPO 1-3 times per week for at least 12 weeks before baseline; Consent to use reliable contraceptive methods and no family planning from the screening period to 3 months after the last administration； Voluntarily participate in the trial and sign the informed consent form. Exclusion Criteria: Patients with a history of severe allergies (including drug allergies), especially allergic to erythropoietin, or to any component of the test drug (e.g. polyethylene glycol); Have a history of kidney transplantation or plan to undergo kidney transplantation during the trial； Have any other disease that causes chronic anemia (e.g., sickle cell anemia, myelodysplastic syndrome, hematologic malignancy, myeloma, hemolytic anemia, pure red cell aplastic anemia) or PRCA following therapy of erythropoietin protein; Suffered from acute or chronic blood loss (such as gastrointestinal bleeding) or undergwent surgical procedures due to massive bleeding within 3 months before screening, or plan to have a surgery during the clinical trial (except for arteriovenous fistula or peritoneal dialysis tube adjustment); Have a history of malignant tumors within the past 5 years (excluding non-melanoma skin cancer or excised carcinoma in situ); Suffer from autoimmune diseases (such as rheumatoid arthritis or systemic lupus erythematosus) or diseases of endocrine system (such as poorly controlled diabetes mellitus complicated with peripheral vascular diseases, severe secondary hyperparathyroidism [parathyroid hormone > 800ng/L]); Received systemic antibiotic treatment or C-reactive protein ≥30mg/L within 4 weeks due to severe infection before screening; The following conditions occur during screening period: Hepatic dysfunction (AST or ALT>3 times ULN); Coagulation dysfunction (activated partial thrombin time > 1.5 times ULN); Folic acid or vitamin B12 deficiency (serum folic acid level <LLN, vitamin B12 <LLN); Positive for HBsAg, HBcAb, HIV-ABb, HCV-AbB or TP-Ab; Suffer from severe thromboembolic disease, poorly controlled severe hypertension (SBP before dialysis > 170mmHg or DBP ≥100mmHg) or hypotension (SBP before dialysis <90mmHg); Suffer from severe cardiovascular and cerebrovascular disease, severe or unstable coronary artery disease, heart failure (NYHA CLASS III or IV), or those who received coronary artery bypass grafting or percutaneous coronary intervention within 6 months, or those who had a history of myocardial infarction or stroke within 3 months; Received androgen therapy or blood transfusion within 8 weeks before screening period; Received long-acting ESAs within 3 months or HIF-PHI (e.g., rosalat) within 2 weeks before initial administration; Participated in other clinical trials as a subject within 4 weeks before screening period or the duration from the last administration to enrollment was shorter than the 5 half-lives of the drug; Have a history of epileptic seizures or mental illness; Alcoholism, drug abuse or drug addiction Pregnant or breastfeeding; Investigator considers not suitable to enter this trial.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1<br>Recombinant human erythropoietin injection; Weekly dose of short-acting EPO (IU/kg)* 0.004 (conversion coefficient), Q2W for administration. | Biological: Recombinant human erythropoietin injection<br>* The dose of PEG-EPO (CHO cells) is converted according to the average weekly dose of short-acting EPO before randomization (4 weeks before randomization) multiplied by the corresponding conversion coefficient (low conversion coefficient is 0.004, High conversion coefficient is 0.008).<br>|
| Experimental: B1<br>Recombinant human erythropoietin injection; Weekly dose of short-acting EPO (IU/kg)* 0.008 (conversion coefficient), Q2W for administration. | Biological: Recombinant human erythropoietin injection<br>* The dose of PEG-EPO (CHO cells) is converted according to the average weekly dose of short-acting EPO before randomization (4 weeks before randomization) multiplied by the corresponding conversion coefficient (low conversion coefficient is 0.004, High conversion coefficient is 0.008).<br>|
| Experimental: A2<br>Recombinant human erythropoietin injection; Weekly dose of short-acting EPO (IU/kg)* 0.004 (conversion coefficient), Q4W for administration. | Biological: Recombinant human erythropoietin injection<br>* The dose of PEG-EPO (CHO cells) is converted according to the average weekly dose of short-acting EPO before randomization (4 weeks before randomization) multiplied by the corresponding conversion coefficient (low conversion coefficient is 0.004, High conversion coefficient is 0.008).<br>|
| Experimental: B2<br>Recombinant human erythropoietin injection; Weekly dose of short-acting EPO (IU/kg)* 0.008 (conversion coefficient), Q4W for administration. | Biological: Recombinant human erythropoietin injection<br>* The dose of PEG-EPO (CHO cells) is converted according to the average weekly dose of short-acting EPO before randomization (4 weeks before randomization) multiplied by the corresponding conversion coefficient (low conversion coefficient is 0.004, High conversion coefficient is 0.008).<br>|
| Active Comparator: C<br>Human erythropoietin injection；Refer to the product instructions. | Biological: Human erythropoietin injection<br>* Refer to the product instructions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of mean hemoglobin compared to baseline during fixed treatment | Change of mean hemoglobin (Hb) content from baseline during fixed treatment (fixed treatment：week 1 to week 6) | Day1-Day42 | 
| Change of mean hemoglobin during dose adjustment period | Change of mean hemoglobin compared to baseline from week 13 to 18 during dose adjustment period (dose adjustment period: week 7 to week 18/week 20). | Day85-Day126 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with hemoglobin keeping within the target range | Proportion of patients with hemoglobin keeping within the target range (target range: the variation from baseline Hb is within ±10g/L, and HB is in the range of 100-130g/L) during treatment period (fixed treatment, week 13 to 18 during dose adjustment period). | Day1-Day42、Day85-Day126 | 
| Reticulocyte count, Hematocrit, Erythrocyte count | Changes of mean values of other evaluation indexes (including HCT, RET, RBC) between baseline and different stages of treatment (fixed treatment period, week 13 to 18 of dose adjustment period). | Day1-Day42、Day85-Day126 | 
| Proportion of patients receiving red blood cell transfusion and number of transfusions during the trial. |  | Day1-Day126/140 | 
| Number of iron deficiency, number of patients and proportion of patients with iron deficiency during the trial | Iron deficiency was defined as SF≤100μg/L and TSAT≤20% in peritoneal dialysis subjects; SF≤200μg/L and TSAT≤20% in hemodialysis subjects. | Day1-Day126/140 | 
| The number and proportion of patients with dose adjustments during the trial |  | Day1-Day126/140 | 
| Anti-drug antibody | The incidence of ADA and Nab | 1,5, 9, 13, 17 weeks (before administration) and 28±2 days after the last administration (A2/B2group ,A1/B1 patients with intensive blood collection) or 14±2 days after the last administration (A1/B1 patients with sparse blood collection) | 
| Adverse events | Any adverse event that occurred during the clinical trials of all patients. | Day1-Day126/140 | 
| Cmax | Maximum observed plasma concentration of EPO. | Day1-Day126/140 | 
| Tmax | Time to maximum observed plasma concentration of EPO. | Day1-Day126/140 | 
| AUC 0-t | Area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration of EPO. | Day1-Day126/140 | 
| AUC 0-∞ | Area under the plasma concentration-time curve from time 0 to infinity. | Day1-Day126/140 | 
| Emax | Maximal effect concentriation | Day1-Day126/140 | 
| Tmax of Emax | Time to maximal effect concentriation | Day1-Day126/140 | 
| AUE0-t | Area under the plasma effect-concentriation curve from time 0 to the time of the last measurable concentration of EPO. | Day1-Day126/140 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PEG-EPO