Pharmacokinetic/Pharmacodynamic Parameters of NNG-DEPO (Stimus) With Aranesp® (Amgen) in Treatment of Anemia in CKD Patients on Dialysis

Study Overview
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Brief Summary
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This is a double-blind, randomized, active-control study with 2-study arms-darbepoetin alfa biosimilar and Aranesp, noninferiority trial design in dialysis patients. Dialysis patients will be randomized into 1:1 ratio to receive either Darbepoetin alfa or Aranesp 0.75 µg/kg by subcutaneous injection every other week for 24 weeks. Pharmacokinetic/pharmacodynamic parameters for evaluation are assessed as per study endpoints at defined time points on all patients. During the treatment, dose adjustments will be made as necessary to achieve a hemoglobin response, defined as maintaining Hb in target range 10 - 12 g/dL.

Detailed Description
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PHASE OF TRIAL: I SAMPLE SIZE: 43 for pharmacokinetic/pharmacodynamic parameters TARGET POPULATION: Patients with chronic kidney disease undergoing dialysis STUDY GROUPS: Darbepoetin alfa (Nanogen) SC 0.75 µg/kg Q2W, for 24 weeks. Aranesp® (Amgen) SC 0.75 µg/kg Q2W, for 24 weeks. PK ASSESSMENT: Blood samples for PK assessments will be collected at: IV: time zero (predose) before injection of study drug and then after 0.25, 0.5, 4, 12, 24, 48, 96, 144, 240 and 336 hours post-dose. SC: time zero (predose) before injection of study drug and then after 4, 12, 24, 48, 96, 144, 240 and 336 hours post-dose. PD ASSESSMENT: Blood samples for PD assessments will be collected at time zero (predose) before injection of study drug and then after 24, 48, 96, 144, 240 and 336 hours post-dose. SAFETY AND TOLERABILITY ASSESSMENT: Safety and tolerability assessments will be performed at each visit. Following variables will be considered to define the safety and tolerability of investigational drugs: Clinical adverse events (AEs): frequency of AEs, overall and by intensity. Severe clinical adverse events (SAEs): frequency of AEs, overall and by intensity. Symptoms directed physical examination including body weight, and vital signs during treatment period: mean change from baseline and the frequency of clinically relevant changes from baseline. Laboratory tests: frequency of clinically relevant changes from baseline. The frequency of any concomitant medication administered to treat any adverse events. Presence of anti-bodies to darbepoetin alfa (immunogenicity).

Official Title
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Randomized, Double-blind, Parallel, Active Controlled Study to Compare Pharmacokinetic/Pharmacodynamic Parameters of Nanogen's Darbepoetin Alfa With Aranesp® (Amgen) in Treatment of Anemia in Chronic Kidney Disease Patients on Dialysis

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Biological: Stimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria The patients signed the informe consent form and adhere to study visit schedule. Male or female patients aged from 18 to 65 years. Patients on hemodialysis or peritoneal dialysis for at least 3 months and have Hb baseline <10 g/dL during the screening period. Have transferrin saturation ≥ 20%, serum ferritin ≥ 200 ng/mL, vitamin B12 and folate within the normal range. Have expected survival of at least 6 months from time of enrollment (by investigator's assessment). Women childbearing age must agree to use medically acceptable methods of contraception during the study and for 6 months after the last study treatment. The patient does not have any serious medical conditions that may affect to study treatment compliance. Exclusion Criteria Uncontrolled hypertension over 2 weeks prior to and within the screening period (BP ≥ 160/90 mmHg). Patients treated with Darbepoetin alfa or r-HuEPO within 4 weeks prior to enrollment. Patients with Uncontrolled diabetes mellitus with HbA1C ≥ 10%. Congestive Heart Failure of grade 3 or 4 as New York Heart Association classification. History of unstable angina or myocardial infarction within 6 months. History of Grand mal seizures in last 2 years. Present with severe hyperparathyroidism (iPTH >1500 pg/mL for Dialysis). History of major surgery within 12 weeks prior to screening. Systemic hematologic disorders including sickle cell anemia, myelodysplastic syndromes, hematological malignancy, myeloma and hemolytic anemia. Systemic infections, active inflammatory diseases and malignancies. Active liver disease or hepatic with liver enzymes AST and ALT raised > 2-times of laboratory normal values, child B or child C cirrhosis. Are being treated with androgen therapy within the 8 weeks prior to the screening period. Pregnant or suspected pregnant women, breast-feeding women. Patients scheduled for any transplant procedure within 6 months of screening or with a previous history of kidney transplantation. Patients who are hypersensitive to any of substances of investigational product. Patients using drugs that can affect the concentration of Hb in the blood (except blood-forming drugs such as iron, folic acid). Patients with seropositivity to HIV, HBV or anti-HCV. Patients having acute tuberculosis or any acute bacterial infection within 1 month prior to the screening. Patient has occult blood in stool or any other known source of internal bleeding and confirmed gastrointestinal bleeding by endoscopy. Patients with blood transfusion due to acute bleeding within 12 weeks prior to screening period. Patients with a history of immunosuppressive therapy within 1 month. The patient is suffering from advanced cancer. Patients having participated in any other clinical trial within 1 month prior to the screening period. The patient had any medical condition that the investigator assessed as affecting the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stimus<br>Treatment: Nanogen's Darbepoetin alfa 10µg/0.4mL, 20µg/0.5mL, 40µg/0.4mL, 60µg/0.3mL, prefilled syringe | Biological: Stimus<br>* NNG-DEPO (Darbepoetin alfa 10 mcg/0.4 mL, 20 mcg/0.5 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL) is available as a prefilled syringe in a sterile, colorless, glass tube. Aranesp® (Darbepoetin alfa 10 mcg/ 0.4 mL, 20 mcg/ 0.5 mL, 40 mcg/ 0.4 mL, 60 mcg/ 0.3 mL) is manufactured by Amgen, as a pre-filled syringe in a sterile, glass tube, colourless. Storage: 2-8ºC, not frozen. The process of transporting and storing the drug must ensure the temperature in the range of 2-8ºC. NNG-DEPO/Aranesp is administered subcutaneously (or intravenously for patients with PK-PD in the previous IV group), at a dose of 0.75 g/kg initially, every 2 weeks at the second visit. IPs will be prepared according to standard procedure (SOP). Dosage adjustment guideline: Patients will have hemoglobin levels monitored every 2 weeks. The investigators will evaluate and adjust the dose of Darbepoetin alfa to maintain the Hb levels within the target range (10 - 12 g/dL)<br>|
| Active Comparator: Aranesp<br>Control: Amgen's Aranesp® 10µg/0.4mL, 20µg/0.5mL, 40µg/0.4mL, 60µg/0.3mL, prefilled syringe | Biological: Stimus<br>* NNG-DEPO (Darbepoetin alfa 10 mcg/0.4 mL, 20 mcg/0.5 mL, 40 mcg/0.4 mL, 60 mcg/0.3 mL) is available as a prefilled syringe in a sterile, colorless, glass tube. Aranesp® (Darbepoetin alfa 10 mcg/ 0.4 mL, 20 mcg/ 0.5 mL, 40 mcg/ 0.4 mL, 60 mcg/ 0.3 mL) is manufactured by Amgen, as a pre-filled syringe in a sterile, glass tube, colourless. Storage: 2-8ºC, not frozen. The process of transporting and storing the drug must ensure the temperature in the range of 2-8ºC. NNG-DEPO/Aranesp is administered subcutaneously (or intravenously for patients with PK-PD in the previous IV group), at a dose of 0.75 g/kg initially, every 2 weeks at the second visit. IPs will be prepared according to standard procedure (SOP). Dosage adjustment guideline: Patients will have hemoglobin levels monitored every 2 weeks. The investigators will evaluate and adjust the dose of Darbepoetin alfa to maintain the Hb levels within the target range (10 - 12 g/dL)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters comparison between NNG-DEPO and Aranesp®: Cmax | Serum peak concentrations (Cmax) | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®: AUC(0, t) | Area under the curve from 0 to t (AUC 0-t) | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PD parameters comparison between NNG-DEPO and Aranesp®: Cmax of reticulocytes | Serum peak concentrations (Cmax) of reticulocytes | Assessed predose and at and at 24;48;96;144;240;336 hours postdose | 
| PD parameters comparison between NNG-DEPO and Aranesp®: AUC(0, t) of reticulocytes | Area under the curve from 0 to t (AUC 0-t) of reticulocytes | Assessed predose and at and at 24;48;96;144;240;336 hours postdose | 
| PD parameters comparison between NNG-DEPO and Aranesp®: Tmax of reticulocytes | Time for the drug to reach peak concentration (Tmax) of reticulocytes | Assessed predose and at and at 24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®:Tmax | Time for the drug to reach peak concentration (Tmax) | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®: AUC(0,∞) | Area under the curve from 0 to ∞ (AUC0-∞) | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®:T1/2 | Half-life (T1/2) | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®: CL/F | CL/F | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®:Vz/F | Vz/F | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| PK parameters comparison between NNG-DEPO and Aranesp®: λz. | λz. | IV:Assessed predose and at 0.25; 0.5; 4;12;24;48;96;144;240;336 hours postdose/ SC: Assessed predose and at 4;12;24;48;96;144;240;336 hours postdose | 
| Proportion of the adverse events (AE) including physical examinations, vital signs, and clinical laboratory investigations. | Rate of AE and SAE occurence | Week 0 (Assessed predose)- Week 24] | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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darbepoetin alfa, Nanogen, CKD, dialysis, treatment of anemia