Comparing Efficacy and Safety of CinnaGen Beta Erythropoietin (CinnaPoietin®) Versus Eprex® on the Treatment of Anemia in ESRD Hemodialysis Patients

Study Overview
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Brief Summary
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This Phase III, randomized, two-armed, parallel, double-blind, active-controlled clinical trial is designed to compare efficacy and safety of CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on the treatment of anemia in 156 End-Stage Renal Disease hemodialysis patients. 156 patients have been planned to randomize and assign to receive CinnaPoietin® or Eprex® for a 26-week period. Administration dose for patients who are treated with erythropoietin is the similar dose of the previously administered amount (IV or SC without any change). After then, dose adjustment will be made based on patients' response. The primary objective of this study is to compare the efficacy of CinnaPoietin® with Eprex®. The secondary objectives of this study are further comparison and evaluation of efficacy along with safety between CinnaPoietin® and Eprex®.

Detailed Description
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This study is a phase III, randomized, two-armed, parallel, double-blind (patient and assessor blinded), active-controlled noninferiority clinical trial to determine the non-inferior therapeutic efficacy and safety between CinnaPoietin® (Beta erythropoietin) and Eprex® (epoetin alpha) on the treatment of anemia in ESRD patient under hemodialysis. After signing the written informed consents, 156 patients have been planned to randomize and assign to receive CinnaPoietin® or Eprex® for a 26-weeks period. Administration dose for patients who are treated with erythropoietin is the similar dose of the previously administered amount (IV or SC without any change). After then, dose adjustment will be made based on patients' response. In addition to main intervention, Nephrovit tablet/day and B12 100 mcg/month were prescribed for patients. The primary objective of this study is to compare the efficacy of CinnaPoietin® with Eprex®. The secondary objectives of this study are further comparison and evaluation of efficacy and safety. The clinical trial will be conducted according to the GCP considerations. A comprehensive validation check program is used to verify the data, and discrepancy reports are generated accordingly for resolution by the investigator. In order to ensure the use of standard and unified procedure of each test, monitoring of each site and laboratory site are going to be applied by sponsor monitoring team and CRO as external monitoring team. The same prefilled syringe is used for CinnaPoietin® to be sure that there is no difference between CinnaPoietin® and Eprex® as brand drug. The drugs will be relabeled, and the same label is used for both prefilled syringe. So neither investigators nor subjects are able to notice any differences between them and are blind to the assignment. Determination of sample size 156 patients will be equally (1:1) divided into intervention arms (78 in each group considering drop out) for achieving 80% power in order to determine non-inferiority using a one-sided, independent sample t-test. The margin of non-inferiority is -1.00. The true difference between the means is assumed to be -0.500. The significance level (alpha) of the test is 0.05. The data are drawn from populations with standard deviations of 1.200 and 1.200.

Official Title
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A Phase III, Randomized, Two Armed, Parallel, Double Blind (Patient and Assessor Blinded), Active Controlled Non Inferiority Clinical Trial to Determine the Non Inferior Therapeutic Efficacy and Safety Between CinnaPoietin® (Beta Erythropoietin) and Eprex® (Epoetin Alpha) on the Treatment of Anemia in ESRD Hemodialysis Patients

Conditions
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Anemia in End-Stage Renal Disease

Intervention / Treatment
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* Drug: CinnaPoietin®
* Drug: Eprex®
* Drug: Nephrovit
* Drug: Vitamin B12 Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18 and 70 ESRD patients who are on hemodialysis for ≥3 months. Hb level 8- 11.5 g/dl Patients are on adequate hemodialysis: the minimally adequate dose of hemodialysis given 3 times per week should be a spKt/V (single-pool delivered Kt/V; clearance of urea x dialysis time/volume of distribution) of 1.2 per dialysis. For treatment periods of less than 5 hours, an alternative minimum dose is a urea reduction rate (URR) of 65%. All types of hemodialysis systems and hemodiafiltration, including high-flux membranes are allowed as long as there is no plan to change the patient's regimen during the study. Sufficient iron stores, defined as serum ferritin ≥ 200 ng/ml and transferrin saturation ≥20%. (Patients not meeting these criteria may receive iron supplementation therapy during the Screening and stabilization period to appropriately correct their iron store deficiency to meet the criterion required for randomization); Ability to comply with study medication use, study visits, and study procedures as judged by the investigator; Females of childbearing potential agree to use an acceptable method of birth control (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD) for the duration of the study. Qualified and willing to sign the informed consent form with the commitment of complying with all the scheduled visits, and study procedures as judged by the investigator; In any circumstances that potential participants are not able to give consent, it may be given by responsible parents or guardian. Exclusion Criteria: Uncontrolled hypertension (defined as pre-dialysis diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥180 mmHg); Anemia secondary to other causes different to the CKD (e.g. multiple myeloma, aplastic anemia, leukemia;….) Decompensated liver failure; Clinical evidence of concurrent uncontrolled hyperparathyroidism (defined as serum parathyroid hormone (iPTH) > 800 pg/ml); Heart failure [New York Heart Association (NYHA) class III and IV]; Unstable angina pectoris, active cardiac disease, stroke and/or cardiac infarction within the last 6 months; History of or active blood coagulation disorders including DVT, PTE, native access Thrombosis during last 6 months. Thrombocytosis (platelet count > 500,000/µl); Thrombocytopenia (platelet count < 100,000/µl); White blood cell count < 3,000/µl); White blood cell count >15,000/µl) Recent Bleeding (acute or chronic bleeding within three months prior to screening); Suspicion of or confirmed occult bleeding (increased reticulocyte count); Clinical evidence of concurrent systemic infection, or inflammatory disease (e.g; diabetic foot, bed sore, access infection, CRP> 30 mg/l,…) Currently receiving treatment for epilepsy; Major surgery within 3 months prior to randomization and during the conduct of the trial (except vascular access surgery); Concomitant immunosuppressive therapy; patients on a short course of steroids (up to 7 days), topical or intranasal steroids are allowed in the study; History of any malignant disease within the last 5 years (except excised non-melanoma skin cancer); Women who are pregnant or breastfeeding; Known history of severe drug-related allergies; Known history of drug related allergy to Erythropoietin or one of the ingredients of the test or the reference products or hypersensitivity to mammalian-derived products; Transplant received within one year prior to the start of the study; Simultaneous participation in another clinical study or having received an Investigational Medicinal Product within three months before randomization in this study. Psychiatric, addictive (drugs or alcohol) or any other disorder that compromises the ability to give an informed consent; Any red blood cell transfusion during the last 3 months (measured at the time of eligibility verification); Primary hematological disorder (e.g. myelodysplastic syndrome, myeloma, sickle cell anemia, hematological malignancy, multiple myeloma hemolytic anemia); known resistance to the rHuEPO defined by a requirement > 450 IU/kg/week by IV or 300 IU/kg/week by SC, equivalent to approximately 20.000 IU/week SC and in absence of iron deficiency; who have suffered an event of active bleeding in the 30 days prior to the beginning of the study; Morbid obesity, defined by a Body Mass Index (BMI) > 37 kg/m2 in women and > 40 kg/m2 in men.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CinnaPoietin®<br>The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response. In addition to main intervention, Nephrovit tablet/day and vitamine B12 100 mcg/month will be prescribed for patients. | Drug: CinnaPoietin®<br>* The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response.<br>* Other names: Beta erythropoietin;Drug: Nephrovit<br>* Nephrovit tablet is daily administered to all the patients.<br>Drug: Vitamin B12 Injection<br>* Vitamin B12 is monthly injected to all the patients.<br>|
| Active Comparator: Eprex®<br>The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response. In addition to main intervention, Nephrovit tablet/day and vitamine B12 100 mcg/month will be prescribed for patients. | Drug: Eprex®<br>* The starting dose of Erythropoietin is 60 (50-100) IU/kg body weight/week for naïve patients. Administration dose for patients who are treated with erythropoietin is similar dose of previously administered amount (IV or SC without any change). After then, dose adjustment will be done based on patients' response.<br>* Other names: Epoetin alpha;Drug: Nephrovit<br>* Nephrovit tablet is daily administered to all the patients.<br>Drug: Vitamin B12 Injection<br>* Vitamin B12 is monthly injected to all the patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Hb Change Level During the Last Four Weeks of Treatment | The primary endpoints of this study is to assess mean Hb change level during the last four weeks of treatment. | Week 22 to week 26 | 
| Mean Weekly Epoetin Dosage Per kg Body Weight During the Last Four Weeks of Treatment | The mean weekly epoetin dosage per kg body weight during the last four weeks of treatment necessary to maintain the Hb level within 10-12 g/dl during the last four weeks of treatment is considered as the second primary endpoint. | Week 22 to week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients With Any Permanent or Transient Dose Change | The proportion of patients with any permanent or transient dose change during 26 weeks. | 26 weeks | 
| The Proportion of Patients With Any Hb Measurement Outside the Target Range (10-12 g/dl) | The proportion of patients with any Hb measurement outside the target range (10-12 g/dl) during 26 weeks. | 26 weeks | 
| The Proportion of Patients Needed Blood Transfusions | The proportion of patients needed blood transfusions during 26 weeks. | 26 weeks | 
| The Proportion of Patients With Treatment Success | Treatment success is considered as Hb concentration equal to or more than 11.0 g/dl and two consecutive weeks without any blood transfusion within the preceding three months | Week 12 to week 26 | 
| The Proportion of Patients With Maintenance Success | Maintenance success is considered as maintenance success is considered as maintenance of mean Hb concentration of 11.0 ± 1.0 g/dl for at least four consecutive weeks | 26 weeks | 
| The Percentage of Patients With Hb Measurements More Than 10.0 g/dl | The percentage of patients with Hb measurements more than 10.0 g/dl from week 22 to week 26. | Week 22 to week 26 | 
| The Percentage of Patients With Hematocrit Measurements More Than 30% | The percentage of patients with hematocrit measurements more than 30% from week 22 to week 26. | Week 22 to week 26 | 
| The Incidence of Hb Levels Above 13 g/dl | The first safety endpoint is the proportion of patients with at least one Hb measurement above 13 g/dL. | 26 weeks | 
| The Proportion of Patients With an Increase in Hb Concentration of > 1.0 g/dl for Four Consecutive Weeks | The proportion of patients with an increase in Hb concentration of > 1.0 g/dl for four consecutive weeks during 26 weeks. | 26 weeks | 
| The Incidence of Adverse Events | The incidence of adverse events during 26 weeks. | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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End-Stage Renal Disease, Anemia, Erythropoietin, Hemoglobin